Fluorine in Organic Chemistry

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page i

Fluorine in Organic Chemistry

Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page iii

Fluorine in Organic Chemistry Richard D. Chambers FRS Emeritus Professor of Chemistry University of Durham, UK

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ß 2004 by Blackwell Publishing Ltd Editorial offices: Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Tel: þ44 (0)1865 776868 Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia Tel: þ61 (0)3 8359 1011 ISBN 1-4051-0787-1 Published in the USA and Canada (only) by CRC Press LLC, 2000 Corporate Blvd., N.W., Boca Raton, FL 33431, USA Orders from the USA and Canada (only) to CRC Press LLC USA and Canada only: ISBN 0-8493-1790-8 The right of the Author to be identified as the Author of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe. First published 2004 Library of Congress Cataloging-in-Publication Data is available A catalogue record for this title is available from the British Library Set in 10/12.5 pt Times by Kolam Information Services Pvt. Ltd, Pondicherry, India Printed and bound in India by Gopsons Papers Ltd, Noida The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards. For further information on Blackwell Publishing, visit our website: www.blackwellpublishing.com

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page v

To my wife Anne and our grandchildren, Daniel, Benjamin, Alexandra, and Jack, who give us so much pleasure

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page vii

Contents

Foreword by Professor George A. Olah Preface 1 I

GENERAL DISCUSSION OF ORGANIC FLUORINE CHEMISTRY

General introduction A Properties B Historical development II Industrial applications A Introduction B Compounds and materials of high thermal and chemical stability 1 Inert fluids 2 Polymers C Biological applications 1 Volatile anaesthetics 2 Pharmaceuticals 3 Imaging techniques 4 Plant protection agents D Biotransformations of fluorinated compounds E Applications of unique properties 1 Surfactants 2 Textile treatments 3 Dyes III Electronic effects in fluorocarbon systems A Saturated systems B Unsaturated systems C Positively charged species D Negatively charged species E Free radicals IV Nomenclature A Systems of nomenclature B Haloalkanes References

xv xvii 1 1 1 2 3 3 3 4 5 5 6 7 7 9 9 12 12 12 12 13 14 14 15 15 16 16 17 18 19

vii

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2

Contents

PREPARATION OF HIGHLY FLUORINATED COMPOUNDS

I

23

Introduction A Source of fluorine II Fluorination with metal fluorides A Swarts reaction and related processes (halogen exchange using HF) 1 Haloalkanes 2 Influence of substituent groups B Alkali metal fluorides 1 Source of fluoride ion 2 Displacements at saturated carbon 3 Displacements involving unsaturated carbon Alkene derivatives Aromatic compounds C High-valency metal fluorides 1 Cobalt trifluoride and metal tetrafluorocobaltates III Electrochemical fluorination (ECF) IV Fluorination with elemental fluorine A Fluorine generation B Reactions C Control of fluorination 1 Dilution with inert gases D Fluorinated carbon E Fluorination of compounds containing functional groups V Halogen fluorides References

23 23 23 24 25 26 27 28 29 30 30 31 31 32 33 35 35 35 36 36 39 39 40 41

3

PARTIAL OR SELECTIVE FLUORINATION

47

I II

Introduction Displacement of halogen by fluoride ion A Silver fluoride B Alkali metal fluorides C Other sources of fluoride ion D Miscellaneous reagents Replacement of hydrogen by fluorine A Elemental fluorine 1 Elemental fluorine as an electrophile B Electrophilic fluorinating agents containing O–F bonds C Electrophilic fluorinating agents containing N–F bonds D Xenon difluoride E Miscellaneous Fluorination of oxygen-containing functional groups A Replacement of hydroxyl groups by fluorine 1 Pyridinium poly(hydrogen fluoride) – Olah’s reagent 2 Diethylaminosulphur trifluoride (DAST) and related reagents 3 Fluoroalkylamine reagents (FARs)

47 47 47 47 49 50 51 51 52 56 58 60 60 62 62 62 63 65

III

IV

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Contents

B C

Replacement of ester and related groups by fluorine Fluorination of carbonyl and related compounds 1 Sulphur tetrafluoride and derivatives D Cleavage of ethers and epoxides V Fluorination of sulphur-containing functional groups VI Fluorination of nitrogen-containing functional groups A Fluorodediazotisation B Ring opening of azirines and aziridines C Miscellaneous VII Addition to alkenes and alkynes A Addition of hydrogen fluoride B Direct addition of fluorine C Indirect addition of fluorine D Halofluorination E Addition of fluorine and oxygen groups F Other additions References 4 I II III

THE INFLUENCE OF FLUORINE OR FLUOROCARBON GROUPS ON SOME REACTION CENTRES

Introduction Steric effects Electronic effects of polyfluoroalkyl groups A Saturated systems 1 Strengths of Acids 2 Bases B Unsaturated systems 1 Apparent resonance effects 2 Inductive and field effects IV The perfluoroalkyl effect V Strengths of unsaturated fluoro-acids and -bases VI Fluorocarbocations A Effect of fluorine as a substituent in the ring on electrophilic aromatic substitution B Electrophilic additions to fluoroalkenes C Relatively stable fluorinated carbocations 1 Fluoromethyl cations D Effect of fluorine atoms not directly conjugated with the carbocation centre VII Fluorocarbanions A Fluorine atoms attached to the carbanion centre B Fluorine atoms and fluoroalkyl substituents adjacent to the carbanion centre C Stable perfluorinated carbanions

ix

66 66 66 69 71 73 73 74 75 76 76 77 79 80 82 82 83

91 91 91 92 92 92 93 94 94 97 97 98 99 99 101 102 104 105 107 108 111 112

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Contents

D Acidities of fluorobenzenes and derivatives E Acidities of fluoroalkenes VIII Fluoro radicals A Fluorine atoms and fluoroalkyl groups attached to the radical centre B Stable perfluorinated radicals C Polarity of radicals References 5

NUCLEOPHILIC DISPLACEMENT OF HALOGEN FROM FLUOROCARBON SYSTEMS

Substituent effects of fluorine or fluorocarbon groups on the SN 2 process A Electrophilic perfluoroalkylation II Fluoride ion as a leaving group A Displacement of fluorine from saturated carbon – SN 2 processes 1 Acid catalysis 2 Influence of heteroatoms on fluorine displacement B Displacement of fluorine and halogen from unsaturated carbon – addition–elimination mechanism 1 Substitution in fluoroalkenes 2 Substitution in aromatic compounds References

113 115 115 115 117 117 118

122

I

122 126 128 128 129 131 131 132 133 135

6

ELIMINATION REACTIONS

137

I

b-Elimination of hydrogen halides A Effect of the leaving halogen B Substituent effects C Regiochemistry D Conformational effects E Elimination from polyfluorinated cyclic systems b-Elimination of metal fluorides a-Eliminations: generation and reactivity of fluorocarbenes and polyfluoroalkylcarbenes A Fluorocarbenes 1 From haloforms 2 From halo-ketones and –acids 3 From organometallic compounds 4 From organophosphorous compounds 5 Pyrolysis and fragmentation reactions B Polyfluoroalkylcarbenes C Structure and reactivity of fluorocarbenes and polyfluoroalkylcarbenes

137 137 138 139 140 142 144

II III

147 147 147 149 149 151 151 154 156

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Contents

1 2 References 7 I

II

Fluorocarbenes Polyfluoroalkylcarbenes

POLYFLUOROALKANES, POLYFLUOROALKENES, POLYFLUOROALKYNES AND DERIVATIVES Perfluoroalkanes and perfluorocycloalkanes A Structure and bonding 1 Carbon–fluorine bonds 2 Carbon–carbon bonds B Physical properties C Reactions 1 Hydrolysis 2 Defluorination and functionalisation 3 Fragmentation D Fluorous biphase techniques Perfluoroalkenes A Stability, structure and bonding B Synthesis C Nucleophilic attack 1 Orientation of addition and relative reactivities 2 Reactivity and regiochemistry of nucleophilic attack 3 Products formed 4 Substitution with rearrangement – SN 20 processes 5 Cycloalkenes 6 Fluoride-ion-induced reactions 7 Addition reactions 8 Fluoride-ion-catalysed rearrangements of fluoroalkenes 9 Fluoride-ion-induced oligomerisation reactions 10 Perfluorocycloalkenes D Electrophilic attack E Free-radical additions 1 Orientation of addition and rates of reaction 2 Telomerisation 3 Polymerisation F Cycloadditions 1 Formation of four-membered rings 2 Formation of six-membered rings – Diels–Alder reactions 3 Formation of five-membered rings – 1,3-dipolar cycloaddition reactions 4 Cycloadditions involving heteroatoms G Polyfluorinated conjugated dienes 1 Synthesis 2 Reactions 3 Perfluoroallenes

xi

156 158 159

162 162 162 162 162 163 163 163 164 166 166 167 167 169 171 172 172 176 176 183 185 186 187 188 190 191 196 197 202 203 205 205 209 212 214 214 214 216 218

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Contents

III Fluoroalkynes and (fluoroalkyl)alkynes A Introduction and synthesis B Reactions 1 Perfluoro-2-butyne Formation of polymers and oligomers Reactions with nucleophiles Fluoride-ion-induced reactions Cycloadditions Free-radical additions References 8 I

FUNCTIONAL COMPOUNDS CONTAINING OXYGEN, SULPHUR OR NITROGEN AND THEIR DERIVATIVES

Oxygen derivatives A Carboxylic acids 1 Synthesis 2 Properties and derivatives 3 Trifluoroacetic acid 4 Perfluoroacetic anhydride 5 Peroxytrifluoroacetic acid B Aldehydes and ketones 1 Synthesis 2 Reactions Addition to C5O Reactions with fluoride ion C Perfluoro-alcohols 1 Monohydric alcohols 2 Dihydric alcohols 3 Alkoxides D Fluoroxy compounds E Perfluoro-oxiranes (epoxides) F Peroxides II Sulphur derivatives A Perfluoroalkanesulphonic acids B Sulphides and polysulphides C Sulphur(IV) and sulphur(VI) derivatives D Thiocarbonyl compounds III Nitrogen derivatives A Amines B N–O compounds 1 Nitrosoalkanes 2 Bistrifluoromethyl nitroxide C Aza-alkenes D Azo compounds E Diazo compounds and diazirines References

218 218 222 222 222 223 223 224 226 227

236 236 236 236 238 240 241 242 243 243 243 246 251 254 254 255 257 258 259 264 265 265 270 272 272 275 275 277 277 278 278 284 284 287

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Contents

9

POLYFLUOROAROMATIC COMPOUNDS

I

xiii

296

Synthesis A General considerations B Saturation/re-aromatisation C Substitution processes 1 Replacement of H by F 2 Replacement of 2N2þ by F: the Balz–Schiemann reaction 3 Replacement of 2OH or 2SH by F 4 Replacement of Cl by F II Properties and reactions A General B Nucleophilic aromatic substitution 1 Benzenoid compounds Orientation and reactivity Mechanism 2 Heterocyclic compounds Pyridines and related nitrogen heterocyclic (azabenzenoid) compounds Polysubstitution Acid-induced processes 3 Fluoride-ion-induced reactions Polyfluoroalkylation Other systems 4 Cyclisation reactions C Reactions with electrophilic reagents D Free-radical attack 1 Carbene and nitrene additions E Reactive intermediates 1 Organometallics Lithium and magnesium derivatives Copper compounds 2 Arynes 3 Free radicals 4 Valence isomers Nitrogen derivatives References

296 296 297 298 298 300 300 300 306 306 307 307 310 311 315 315 320 321 325 325 332 332 336 338 338 341 341 342 346 346 349 351 353 358

10

ORGANOMETALLIC COMPOUNDS

365

I

General methods and synthesis A From iodides, bromides and hydro compounds 1 Perfluoroalkyl derivatives 2 Derivatives of unsaturated systems

365 365 365 366

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xiv

Contents

B

From unsaturated fluorocarbons 1 Fluoride-ion-initiated reactions II Lithium and magnesium A From saturated compounds B From alkenes C From trifluoropropyne D From polyfluoro-aromatic compounds III Zinc and mercury A Zinc B Mercury 1 Perfluoroalkyl derivatives 2 Unsaturated derivatives 3 Cleavage by electrophiles IV Boron and aluminium A Boron 1 Perfluoroalkyl derivatives 2 Unsaturated derivatives B Aluminium V Silicon and tin A Silicon B Tin VI Transition metals A Copper B Other metals References

367 367 368 368 369 370 371 371 371 373 373 374 375 376 376 376 377 380 381 381 385 387 388 388 395

Index

399

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Foreword by Professor George A. Olah Nobel Laureate

Chambers’ book Fluorine in Organic Chemistry was published 30 years ago and became a classic of the field. A revised and updated edition is a significant and authoritative contribution by one of the leaders of organic fluorine chemistry. Organic fluorine chemistry has grown enormously in significance and scope in the intervening three decades, not in small measure by the contribution of the author and his colleagues. The new edition will be of great value and help not only to those interested in fluorine chemistry, but also to the wider chemical community. When considering a new edition of a ‘classic’ of chemical literature, it is most appropriate to maintain broadly the layout and aims of the original book, concentrating on methodology, mechanism and the unique chemistry of highly fluorinated compounds. Understandably, therefore, it is outside the scope to discuss medicinal and biochemical aspects. Readers interested in these topics are advised to use the extensive reviews that are available elsewhere.

xv

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Preface

This book is a revision and update of one that was first published in 1973, followed by two small reprintings. The original was prompted by Professor George Olah, during a year that I spent as a Visiting Lecturer in Cleveland. My aim for the original edition was to present an overview of organofluorine chemistry, in a way that corresponded with modern organic chemistry. Of course this involved including a mechanistic basis of the subject, which was still evolving at the time; to my knowledge, this was the first broad attempt to do so. The original book appears to have served a useful purpose because, for a number of years now, friends in the field have encouraged me to write an update. In the intervening years since the first edition the subject has grown enormously, and any idea of a single-author comprehensive volume would now be a preposterous undertaking. Consequently, I have concentrated attention on illustrating the principles of the subject, and especially those concerning highly fluorinated compounds, where the chemistry is quite unusual. Inevitably, important areas are omitted: for example the impact of fluorine as a label in biochemistry, which is outside my expertise. However, I hope that there are enough key references to important areas that I have neglected. Inevitably, my choice of illustrative examples is subjective and I apologise in advance for all the beautiful examples that have not been included. The considerable task of producing the manuscript would not have been completed without the continued help of a long-term friend and collaborator, Dr. John Hutchinson, to whom I am deeply indebted. Also, my sincere thanks to the Leverhulme Trust for an Emeritus Fellowship, during the tenure of which the book was written. Thanks also to my colleague, Dr Graham Sandford, for invaluable help and discussions, and to Dr Darren Holling, Rachel Slater and Chris Hargreaves for reading the manuscript. Last, but not least, thanks to my wife Anne for her continued forbearance. Dick Chambers

xvii

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Chapter 1

General Discussion of Organic Fluorine Chemistry

I

GENERAL INTRODUCTION

One of the major activities of chemists in industry and academia is the search for ‘specialeffect’ chemicals, i.e. systems with new chemistry and with novel properties that can be exploited by industry. There are, of course, many ways of creating novel systems but the introduction of carbon–fluorine bonds into organic compounds has led to spectacular industrial developments, together with an exciting field of organic chemistry and biochemistry. Fluorine is unique in that it is possible to replace hydrogen by fluorine in organic compounds without gross distortion of the geometry of the system but, surprisingly, compounds containing carbon–fluorine bonds are rare in nature [1, 2]. In principle, therefore, we could introduce carbon–fluorine bonds singly, or multiply, so that there is the potential for a vast extension to organic chemistry, providing that the appropriate methodology can be developed. Consequently, the study of systems containing carbon– fluorine bonds has become a very important area of research and the subject already constitutes a major branch of organic chemistry, while imposing a strenuous test on our fundamental theories and mechanisms. Moreover, as we shall see later in this chapter, the applications of fluorine-containing organic compounds span virtually the whole range of the chemical and life-science industries and it is quite clear that wherever organic chemistry, biochemistry and chemical industry progress, fluorine-containing compounds will have an important role to play. Surprisingly, this situation is still not reflected in current general textbooks; the reasons can be traced partly to the very rapid growth of the subject, as well as the difficulty that all workers experience in reaching a wider audience. Therefore, it is hoped that this book will help by presenting an outline of fluorine chemistry on a broadly mechanistic basis. This volume stems from an earlier book [3] on the subject; its aim remains to provide an overview through highlighting a variety of topics but with no attempt to provide comprehensive coverage of the literature. Where appropriate, books and reviews will be cited and the author therefore acknowledges the many sources, referred to either here or in the following text, to which this book is intended to be complementary [4–39].

A

Properties

Fluorocarbon systems, in general, present no peculiar handling difficulties and the familiar and powerful techniques of isolation, purification and identification in organic Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

1

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2

Chapter 1

chemistry are applicable in every way. In fact, fluorocarbons themselves are characterised by high thermal stability and, indeed, elemental fluorine is so very reactive because it forms such strong bonds with other elements, including carbon. Volatilities of hydrocarbons and corresponding fluorocarbons are surprisingly similar, despite the increased molecular weight of the latter, and indicate a general feature that intermolecular bonding forces are reduced in the perfluorocarbon systems. A final, and by no means least important, similarity between hydrocarbon and fluorocarbon chemistry is that, like hydrogen-1, fluorine-19 has a nuclear spin quantum number of 1/2 and so nuclear magnetic resonance spectroscopy plays a powerful role in characterisation [40]. Indeed, the only tool that is not easily available for fluorine is the observation of fluorine isotope effects, because the longest-lived isotope is F-18, with a half-life of only 109 minutes [41] although, even with this limitation, applications as a mechanistic probe have been reported [42].

B Historical development It could be argued that fluorocarbon chemistry began with Moissan in 1890 when he claimed to have isolated tetrafluoromethane from the reaction of fluorine with carbon, but these results were in error [43, 44]. Swarts, a Belgian chemist, began his studies on the preparation of fluorocarbon compounds [45] by exchange reactions around 1890 and for about 25 years from 1900 he was virtually the only worker publishing in the field. He continued until about 1938, and during that time he contributed a great deal in outlining methods of preparation for a large number of partly fluorinated compounds. It was on the foundation of Swarts’s work that Midgley and Henne [46] in 1930 were able to apply fluoromethanes and ethanes as refrigerants, and this development gave the subject some financial impetus for progress. Tetrafluoromethane was the first perfluorocarbon to be isolated pure; it was reported in 1926 by Lebeau and Damiens [47] but not properly characterised by them until 1930 [48] and, in the same year, by Ruff and Keim [49]. Swarts made trifluoroacetic acid [50] as early as 1922 and in 1931 reported that the electrolysis of an aqueous solution of the latter gave pure perfluoroethane [51]. Nevertheless, the first liquid perfluorocarbons were not characterised until 1937, when Simons and Block found that mercury promotes reaction between carbon and fluorine [52]; they were able to isolate CF4 , C2 F6 , C3 F8 , C4 F10 (two isomers), cyclo-C6 F12 and C6 F14 . It was established that these compounds are very thermally and chemically stable and this led to suggestions by Simons that these materials might be resistant to UF6 , which was found to be the case. There then ensued a period of very rapid development in the synthesis of fluorocarbon materials, the goal being stable lubricants and gaskets for use in the gaseous diffusion plant for concentrating the 235 U isotope, using UF6 . These wartime developments have been published in various collected forms [53–55]. Tetrafluoroethene was obtained by Ruff and Bretschneider in 1933, who decomposed tetrafluoromethane in an electric arc [56] while Locke et al. [57] developed a synthesis in 1934, which involved zinc dehalogenation of CF2 Cl2CF2 Cl. Then the formation of polytetrafluoroethene [58] was discovered in 1938 and in the same period chlorotrifluoroethene was found to polymerise to give a very stable inert transparent polymer. The wartime efforts involved development of these and other new materials. Nevertheless, even at the end of the

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General Discussion of Organic Fluorine Chemistry

3

wartime work the subject was not well developed as an area of organic chemistry. However, its potential was recognised by a number of workers and, since then, progress has been extremely rapid. In the 1950s much progress was made on the chemistry of functional derivatives and a whole new fluorocarbon organometallic chemistry began to emerge. A major and greatly under-appreciated development of the period was the introduction of fluorinated anaesthetics which, being non-flammable, revolutionised anaesthesia. Also during this period was the development of fluorinated elastomers which, together with other fluorinated materials, were critical in the development of supersonic and space flight. It is clear, therefore, that this infant subject made crucial contributions to some of the most exciting scientific developments of the 20th century. The period from 1960 onwards saw perfluoroaromatic chemistry rapidly unfold, selective methods for fluorination develop, and fluorinated compounds play an increasingly important role in the pharmaceutical and plant-protection industries. Indeed, there have been so many interesting developments in the subject since the original edition [3] that it will be impossible to do justice to this era in one small volume. Remarkably, it has been reported that organofluorine compounds constitute 6–7% of all new compounds recorded in Chemical Abstracts up to 1990 and 7–8% of all chemical patents up to 1997 contain fluorinated compounds. This in itself is an outstanding output for the relatively limited number of workers in the field worldwide and is a tribute to their dedication [59].

II

INDUSTRIAL APPLICATIONS

A

Introduction

Even in 1992, it was estimated that business involving the sale of compounds containing carbon–fluorine bonds was worth around US$50 billion per annum [60] and it has certainly increased since then. In this chapter, only a short survey of the major industrial applications of fluorinated molecules is possible and the reader is directed to a number of books and reviews [17, 20, 29, 61–65] for further details.

B

Compounds and materials of high thermal and chemical stability [29]

The greater strength of the carbon–fluorine over the carbon–hydrogen bond leads to considerably enhanced thermal stability for perfluorocarbon systems over their hydrocarbon analogues, and stability towards oxidation is dramatic. Moreover, the large number of non-bonding p-electrons, which virtually shield the carbon backbone from attack in a perfluorocarbon, must contribute significantly to these properties and, at the same time, produce novel surface effects. Furthermore, perfluorinated systems are quite inert to microbiological attack and so, combining these observations, it is reasonable to conclude that perfluorocarbon surfaces provide the ultimate in organic materials for protection against chemical and atmospheric corrosion. A further unique property of perfluorocarbons is that they are both water- and hydrocarbon-repellent and the implications for fabric treatment are obvious.

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4

Chapter 1

1 Inert fluids The chlorofluorocarbons (CFCs) were introduced over 60 years ago as refrigerants [46] to replace gases such as ammonia and sulphur dioxide. In 1974, at the peak of production, 900 000 tonnes of CFCs, principally CF2 Cl2 (CFC-12), CFCl3 (CFC-11) and CHFCl2 (CFC-22), were manufactured mainly for use as refrigerants, aerosols and foam blowing agents. However, it was eventually recognised that the inertness of volatile CFCs is itself a problem because they survive unchanged up to the stratosphere, where they dissociate under short-wavelength solar ultraviolet radiation, releasing chlorine atoms which then catalyse the decomposition of ozone to oxygen [66, 67]. Consequently, the Montreal Protocol, which was introduced in 1987 and revised in 1990 and 1992, caused the complete phase-out of production and use of the CFC range of compounds. This legislation forced refrigerant manufacturers to identify alternative ranges of non-toxic, stable chemicals which, additionally, possess low ozone depletion potentials (ODPs) and low global warming potentials (GWPs) to meet customer needs and regulatory requirements. Hydrofluorocarbons (HFCs), being free of chorine atoms, have ODPs of zero, making these products ideal systems for replacing CFCs. One of the major unsung achievements of the chemical industry has been the rapid development to large-scale production of these substitutes for CFCs; for example, CF3 CFH2 (HFC-134a) is an acceptable substitute for CF2 Cl2 (CFC-12) in refrigeration applications. Bromofluorocarbons possess outstanding fire-extinguishing ability: CF3 Br has been used for automatic systems where the use of water is as potentially damaging as a fire, for instance in art galleries and in libraries, or in aircraft where highly efficient non-toxic agents are required. However, on an atom-to-atom basis bromine atoms are estimated to be 40 times more effective at destroying ozone than chlorine atoms, and therefore the Montreal Protocol required the complete phase-out of bromofluorocarbon use in 1994. Alternative ‘in-kind’ replacements [68] of these halon fire extinguishers are being developed and currently CHF3 (DuPont) and CF3 CFHCF3 (Great Lakes), amongst others, are on the market [69], but at the time of writing the problem of finding replacements for bromofluorocarbons for application as fire-fighting agents in aircraft is largely unsolved. Perfluorocarbon fluids, such as the Flutect range (F2 Chemicals Ltd), find many uses in the electronics industry. For instance, the complete immersion of electronic components in a bath of perfluorocarbon fluid can efficiently cool overheated circuits and, by a similar process, the airtight packaging around highly valuable and sensitive equipment can be tested in complete safety for leaks. Since perfluorocarbons are inert to microbiological attack, many potential medical uses of these fluids have been investigated. The report by Clark in 1966 that perfluorocarbons can dissolve significant amounts of oxygen [70] prompted the exciting suggestion that such fluids could be used as ‘artificial blood’ [71] and the now-classic photograph of a rat breathing under liquid perfluorocarbon has been reproduced countless times. Perfluorocarbons are immiscible with blood and do not dissolve the essential mineral nutrients required. Consequently, emulsions of perfluorocarbons with an aqueous buffer solution containing various surfactants have been formulated as potential blood substitutes. Although products have been approved and marketed, there is no commercially successful emulsion. The need to extend the liquid range of perfluorinated systems to very high molecular weights was satisfied by the important introduction of perfluoropolyethers (PFPEs) [72]

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General Discussion of Organic Fluorine Chemistry

5

as high-boiling inert fluids, such as Krytoxt (DuPont), Fomblint (Ausimont) and Demnumt (Daikin), for use in demanding environments and for long-term reliability (Figure 1.1). These fluids have the longest liquid range known [73], remaining in fluid form from
1008 C to 3508 C and, consequently, are used for the lubrication of many diverse precision instruments, from the mechanisms of luxury watches to the moving parts of geostationary satellites and even for computer discs. F

CF3

O

OCF2CF2CF2 F

F

n

OCF2

n

Krytox® (DuPont) Lubricants, coatings

Demnum® (Daikin)

n

OCF2CF2

m

Fomblin® (Ausimont)

Lubricants, vacuum pump oils

Figure 1.1

2

Polymers [73a]

Since the first synthesis of polychlorotrifluoroethene and the discovery of polytetrafluoroethene (PTFE) in the late 1930s, the global production of fluoropolymers has grown to over 60 000 tonnes per annum. Fluoropolymers possess a unique combination of properties [74–76] which ensure a wide range and continually growing number of applications for these materials. The fabled ‘non-stick’ properties of PTFE may be attributed to the abundance of non-bonding electron pairs and the coefficient of friction has been related to that of wet ice on wet ice. Some examples of commercial fluoropolymers are listed in Table 1.1 along with just some of the many applications. The remarkable feature of this area is that materials such as Vitont (DuPont) and related elastomers, which were once regarded as esoteric and appropriate in cost only for ‘space flight’ and related applications, have now entered widely into the automobile industry. Lumiflont (Asahi Glass Co., Japan), a high-performance paint which is famously used on the Hikari ‘bullet trains’ in Japan, and various coatings for protection of concrete and stone building materials have also emerged. The gradual public realisation that the higher cost of high-performance products makes longer-term economic sense is the driving force behind the continued growth of this industry. Perfluorinated ionomer membranes [77], such as Nafiont (DuPont) and Flemiont (Daikin), are increasingly being used as cell-dividing membranes for chlor-alkali cells, replacing the mercury cells that have, understandably, led to so much public concern.

C

Biological applications [29, 61, 62]

The physiological properties of many biologically significant molecules can be modulated if fluorine or fluorinated groups are incorporated into their structure [24, 78]; factors affecting the change in biological activity of a substrate upon fluorination are complex [79].

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6

Chapter 1

Table 1.1 Applications of fluoropolymers Polymer

Monomer(s)

Applications

CF2=CF2

PTFE

FEP

CF2=CF2 + CF3CF=CF2

PFA

CF2=CF2 + RFOCF=CF2 F

Teflon AFt (DuPont)

CF2=CF2+ O CF3

F

Optically clear, used in corrosive environments where glass is unsuitable, e.g. in computer chip manufacture. Optically clear, used in corrosive environments, e.g. computer chip manufacture. Gaskets, seals, oils, coatings, transparent inert covers. Weather-resistant coatings; cable insulation; piezo-electric devices. Coatings, flexible films. Elastomers used for sealants, Orings, fuel-resistant seals for aircraft and automobiles.

O CF3

CF2=CFO(CF2)nCF=CF2

Cytopt (Asahi)

PCTFE

CF2=CFCl

PVDF

CF2=CH2 CH2=CHF

PVF VitonAt (DuPont)

CF2=CH2 + CF3CF=CF2 CF2⫽CF2 + F2C⫽C

F

CF3

2

Nafiont (DuPont)

Cookware coatings; Goretext (W.R. Gore Co.) waterproof clothing; electrical insulators; medical uses such as artificial blood vessels. Fabrication by conventional melt processing; wire and cable insulators; heat-sealable film, tubing. Injection-moulded parts for use in aggressive environments.

Membranes in chlor-alkali cells.

⫺

(OCF2CF)nO

CF2CF2X

Flemiont (Daikin)

Nafion, X ¼ CO2 H Flemion, X ¼ SO2 H

1 Volatile anaesthetics Prior to 1956, the most common anaesthetics included diethyl ether and chloroethane, with the associated risks. Fluothanet (ICI) was the first widely used fluorine-containing volatile anaesthetic [80], and such was its success that it has been estimated that 70–80% of all anaesthesias carried out in 1980 were performed using this substance. However, Isofluranet, Sevofluranet and Desfluranet are now commercially available alternatives in the general quest for less readily metabolised systems and faster recovery times of the patients (Figure 1.2).

CF3CHClBr

CF3CHClOCHF2

(CF3)2CHOCH2F

CF3CHFOCHF2

Fluothane®

Isoflurane®

Sevoflurane®

Desflurane®

Figure 1.2

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 7

General Discussion of Organic Fluorine Chemistry

2

7

Pharmaceuticals

Fluorinated corticosteroids were the first successful commercial products where useful modification of biological activity was achieved by introduction of a carbon–fluorine bond. Subsequently, the interest of the pharmaceutical industry in this approach has grown substantially and many new fluorine-containing products are available or are in advanced screening stages. Simplistically, an orally administered drug must: (a) be absorbed through the gut into the bloodstream, (b) then pass through a series of phospholipid membranes (transport) before reaching the correct site of action, and (c) bind and produce the desired effect at the appropriate enzyme site. Following this stage, the drug should be metabolised neither too quickly, nor into toxic by-products. The incorporation of fluorine into a biologically active molecule may modulate all of these functions as well as the more obvious effects of enhancing the acidity or reducing the base strength of appropriate proximate functional groups. Size is not the dominant factor, although steric requirements in biology are not so easy to establish, and a range of factors arising from fluorine substitution are at work [81– 83] and will continue to be evaluated for some considerable time. Fluorine or trifluoromethyl substituents generally enhance the lipophilicity of an aromatic substrate and so increase the rate of transport of the drug to the active site. A contributing factor could be, for example, the change in acidity of the drug upon fluorination, thus enhancing the solubility. Whatever the relative importance of the contributing factors, introduction of a fluorine atom at the C-6 site in the antibacterial fluoroquinolone drugs, e.g. Ciproflaxint (Bayer), increases the rate of cell penetration by up to 70 times. Fluorine substitution in drugs may affect binding in two ways [61]. First, it is often possible to vary the dipole moment (e.g. using two fluorine substituents that are ortho, meta or para in a phenyl group); secondly, it is possible that fluorine may be displaced from the bound drug, leading to covalent binding, in a process referred to as ‘suicide inhibition’. The anti-metabolite 5-fluorouracil (5-FU) is almost certainly effective in part through this process. A further significant effect of introducing fluorine is the resulting enhanced resistance to metabolic oxidation and therefore to potentially toxic by-products, thus increasing both the effective lifetime and the safety of a drug. Some examples of fluorinated pharmaceuticals currently on the healthcare market are given in Figure 1.3. Both Ciprofloxacint (Bayer), a member of the 6-fluoroquinolone antibacterial agent range, and the controversial ‘sunshine drug’ Prozact (Eli Lilley), the leading member of a new family of selective serotonin re-uptake inhibitor (SSRI) antidepressants, are in the world top 20 best-selling pharmaceuticals and achieve annual sales in the region of US$1 billion each.

3

Imaging techniques

The isotope fluorine-18 has a half-life of 109 minutes and decays by positron emission; therefore molecules containing this isotope can be monitored by positron emission tomography (PET), which is a technique that is especially useful for non-invasive in vivo study of metabolic processes [41]. For example, 2-fluorodeoxyglucose is transported into cells in the same manner as glucose but, after rapid phosphorylation, further metabolism is inhibited because of the fluorine, thus effectively trapping the radiolabelled

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8

Chapter 1 O H

O H

CF3

N

F N O N

O

O

N

HO

H OH

5-Fluorouracil (anti-cancer)

N

N

Trifluridine® (anti-viral)

N

O

N

OH

N

N

CO2H

F

F N

N

N H

F Fluconazole® (anti-fungal)

Ciprofloxacin® (antibacterial)

O

H O

OH

HO

N

CH2OH

CH3

CH3

F3C

F O Prozac® (anti-depressant)

Betamethasone® (anti-inflammatory)

Figure 1.3 Examples of drugs containing fluorine

molecule in a cell. Uptake of fluorine-18 gives a direct measure of the rate of glucose metabolism in the part of the body under study. Similarly, 18 F-DOPA acts as a tracer for DOPA, which is a neurotransmitter in the brain, and the PET study of the complex metabolism and biodistribution of DOPA is hoped to provide a quantitative measure of the dopaminergic neurons in the brain [84] (Figure 1.4). Non-invasive monitoring of therapeutic agents can also be performed by 19 F magnetic resonance imaging (MRI); the negligible natural fluorine background and the high sensitivity of 19 F NMR spectroscopy has made possible the study of the in vivo action and metabolic pathways of fluorine-containing drugs. For instance, 19 F MRI has demonstrated that 5-fluorouracil is metabolised to NH2 CH2 CHFCOOH.

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General Discussion of Organic Fluorine Chemistry

9

F

HO

CO2H O

HO

OH HO

F

NH2

HO OH

18F-2-Fluorodeoxyglucose

18F-6-Fluoro-DOPA

(PET Scanning Agent)

(NMR Scanning Agent)

Figure 1.4

Perfluorooctyl bromide is being used very successfully to enhance the contrast between healthy and diseased tissue in 1 H MRI procedures and as a general imaging agent for X-ray and other forms of examination of soft tissue.

4

Plant protection agents [62]

Environmental concerns have imposed massive constraints on plant protection products, and the impressive progress towards lower dose levels for effective control is another of the unrecognised success stories of the chemical industry. Fluorinated molecules have played an important role in these developments, leading to a range of successful herbicides, insecticides and fungicides [85]. Trifluralin (Dow), a herbicide used principally for the control of grassy weeds in a wide range of crops, has been in use for over 25 years and peak sales in the mid 1980s reached US$400 million per annum. Fusiladet is another widely successful herbicide used for the control of weeds in broad-leaf crops at low dosage rates. The pyrethroid derivative Cyhalothrint is a successful insecticide and the fungicide sector contains five significant products with fluorine incorporated in the substrate. Flutriafolt is used for protecting cereal crops and Flutolanilt is used mainly in the Far East for controlling crop diseases (Figure 1.5).

D

Biotransformations of fluorinated compounds

As the occurrence of fluoride ion is so widespread, it is particularly surprising that compounds containing carbon–fluorine bonds are rarely found in nature [1, 2]. Potassium monofluoroacetate occurs in several tropical and sub-tropical plants located in the southern hemisphere, such as Dichapetalum cymosum (South Africa, very toxic to animals) and Oxylobium parviform (Australia). Some plants, such as soya bean (Glycine max), are able to synthesise fluoroacetate when grown in fluoride-rich soil. A shrub occurring in Sierra Leone, Dichapetalum toxicarium (ratsbane), is also poisonous, particularly the seeds, and this has been attributed to the occurrence of v-fluoro-oleic acid, CH2 FðCH2 Þ7 CH5CHðCH2 Þ7 COOH [86]. Nucleocidin, an adenine-containing antibiotic, has been isolated from the fermentation broths of a micro-organism Streptomyces calvus [1]. The fact that only 12 compounds containing C–F bonds have been found in nature so far [87] leads to the questions of (a) whether this is a consequence of the difficulty of forming C–F bonds in the first place, and (b) whether subsequent enzymic transformations in plants and animals are inhibited by the presence of C–F bonds. Fluorine, as fluoride ion, although extremely abundant, is present in largely insoluble salts. Moreover, fluoride ion is extensively hydrated because of the strength of hydrogen bonding, and in

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10

Chapter 1 NnPr2 O

NO2

O2N

O

F3C

OnBu Me

N

CF3

O Fusilade®

Trifluralin® O

CN O

F3C

O

Cl

Cyhalothrin® OH F

CF3 N

O

F

N

N

H

Flutriafol®

Flutolanil®

N

OiPr

Figure 1.5 Examples of plant-protecting agents containing fluorine

the hydrated state it is relatively unreactive as a nucleophile. It seems likely, therefore, that the dearth of C–F bonds in nature is essentially due to a combination of these effects, which inhibit C–F bond formation. However, an exception to this situation is the formation of the toxin fluoroacetate, which inhibits the Krebs cycle. Moreover, O’Hagan and co-workers have successfully identified the first fluorinase enzyme, in the bacterium Streptomyces cattleya, which catalyses the formation of a C–F bond [88] (Figure 1.6). These results then raise the issue of how the fluoride becomes an active nucleophile in this system: at this stage, the most likely scenario is that fluoride ion is drawn into lipophilic sites on the enzyme and effectively de-solvated, to make it more reactive. Exciting prospects for the future are indicated by the identification of this fluorinase system [88]. In contrast, there are now many examples in the literature to indicate that, when presented with organic compounds already labelled with fluorine, enzymes may be tolerant to the presence of fluorine, depending on the number of C–F bonds and their location [89, 90]. For example, baker’s yeast may lead to significant asymmetric reduction of carbonyl (Figure 1.7). Likewise, various kinetic resolutions of fluorinated compounds have been achieved, e.g. the acetate of 1,1,1-trifluoro-2-octanol has been transformed into (R)-1,1,1-trifluoro2-octanol (Figure 1.8).

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General Discussion of Organic Fluorine Chemistry − O

+ H3N

N Me

S

N

+

O

HO

NH2

NH2

O

N

N

−

N

F

½88

N

F

Fluorinase

11

N

N

O

HO

OH

S-adenosylmethionine

OH 5'-FDA

O

O +

NAD

OH

H

F

F Fluoroacetaldehyde

Fluoroacetate

Figure 1.6

½89

OH 58%

CH2FCOPh FH2C

Ph

R (90% ee)

Figure 1.7 OCOMe F3C

CH2CO2Et

OH

Lipase MY F3C

CH2CO2Et

OCOMe F3C

½89

CH2CO2Et

(R) 96% ee

Figure 1.8

The use of CHF [91] and CF2 [92] groups as oxygen mimics has been explored and fluoromethylenephosphonates, as phosphate mimics [93], have been employed as binding agents for a promising approach to catalytic antibodies [94] although inevitably these sites must be more sterically demanding than oxygen. Of course a fluorine atom itself is isoelectronic with an oxygen anion and, not surprisingly, fluorinated carbohydrates have been widely explored [22, 95], as have fluorinated amino-acids and peptides [31, 96]. Indeed, fluorine is advocated as a tool for exploring the conformations of amides and peptides [97]. The presence of fluorine, with the opportunity of observation by 19 F NMR, free from the often complex 1 H signals, can be an extremely useful probe.

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12

Chapter 1

It should be clear from this cursory discussion, and the publications referred to, that the roles of fluorine in drug design and in applications to biochemistry are very large and burgeoning topics that are hugely important.

E

Applications of unique properties

1 Surfactants [29] The low surface energy possessed by highly fluorinated compounds has allowed the development of fluorine-containing surfactants that are especially effective in very low concentrations [98–100]. Surfactants based on straight fluorocarbon chains are the most efficient known, and a terminal trifluoromethyl group is essential to this efficiency. Fluorinated surfactants are used in fire-fighting foams, as emulsifiers for polymerisations and as additives to paints. Cationic, anionic and non-ionic surfactants containing perfluorinated groups have been marketed; examples of each are given in Figure 1.9. F3C F3C C8F17SO2NH(CH2)3NMe3

C2F5

I

Cationic

CF3 O

C2F5

SO3

Na

Anionic

C8F17CH2CH2O(CH2CH2O)nH Non-ionic

Figure 1.9 Fluorinated surfactants

2 Textile treatments [29] Polyacrylates bearing pendant perfluoroalkyl groups are extremely difficult to wet, due to the very low surface energy of the partially fluorinated polymer. When surfaces of materials are coated with such polymers, their oil and water repellencies are greatly enhanced and this has been used to great effect in the textile-finishing area. Products such as Zepelt (DuPont) are used for coating fabrics, as furniture sprays, and as carpet and leather finishing agents. However, the highly successful Scotchgardt (3M) was removed from the marketplace following concerns about the appearance of perfluoro-octyl sulphonic acid in various blood samples, albeit in extremely low concentrations. However, the extreme stability of the acid could lead to a build-up in biological systems. Techniques for plasma polymerisation have been progressed significantly in recent years [101] and direct formation of fluorocarbon coatings on surfaces, including textiles, holds much promise.

3 Dyes [29] Fibre-reactive dyes are water-soluble dyes containing a chromophore that is attached to a reactive group which then may be attacked by fibres containing nucleophiles to form a

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General Discussion of Organic Fluorine Chemistry

13

dye–fibre bond. Fluorinated heterocycles, such as pyrimidines or triazines, are the most widely used ‘carrier systems’ for dye chromophores since the fluorine on the heterocyclic ring may be attacked by hydroxyl groups on the cellulose or cotton fibre surface, as outlined below (Figure 1.10) (see Chapter 9 for a discussion of nucleophilic aromatic NH-Dye Cl

N F

Dye-NH2

Cl

NH-Dye Cl

N

N

N

Cotton-OH

F

F

N

Cotton

O

N

Figure 1.10

substitution of fluorine). The incorporation of trifluoromethyl groups into a chromophore can give the dye increased light fastness and improved clarity. A similar approach to conferring oil-repellency on cellulose surfaces has been described using perfluoro(isopropyl-s-triazine)s [102]. For various reasons, the superior properties of most liquid-crystalline materials contained in LCD displays depend critically on the presence of fluorinated substructures [103]. In particular, perfluorinated groups have displaced cyano groups for their role in inducing polarity.

III

ELECTRONIC EFFECTS IN FLUOROCARBON SYSTEMS

The electronic properties and size of fluorine relative to hydrogen and chlorine are set out in Table 1.2; at this point it is worthwhile to examine some of the possible consequences of these differences for the chemistry of fluorocarbon systems. In this way it can be emphasised, at the outset, how far-reaching these effects will be and, at the same time, it sets the scene for a rational approach to the chemistry. First, the large ionisation energy of fluorine implies that species involving electrondeficient fluorine might be less common than those involving hydrogen or chlorine. The ionisation energy of chlorine is, in fact, less than that of hydrogen and chloronium ions Table 1.2 Electronic properties H Electronic configuration Electronegativity (Pauling)
a Ionisation energy kJmol
1

1 b Electron affinity kJmol Bond energies of
C2X in CX4 kJmol
1 Bond energies
of X2X kJmol
1 ˚) Bond lengths of C2Xc (A ˚ van der Waals radius (A) Preference as a leaving group a b c

Xþ þ e
! X X þ e
! X
Covalent radii in CX4

1

F 2

Cl 5

2

Ref. 5

0

1s 2.20 1312 74.0 446.4

. . . 2s 2p 3.98 1681 332.6 546.0

434

157

242

[105]

1.091 1.20 Hþ

1.319 1.47 F


1.767 1.75 Cl


[19] [104] –

. . . 3s 3p 3d 3.16 1251 348.5 305.0

– [104] [104] [104] [19]

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14

Chapter 1

2Clþ 2 (as well as 2Brþ 2 or 2Iþ 2) are now well established [106], whereas the analogous fluoronium species 2Fþ 2 have not been observed. It is particularly interesting that the electron affinity of fluorine is actually less than that of chlorine because, here, we have the first indication of repulsion between unshared electron pairs raising the energy of the system, and it is likely that this factor accounts for the lower bond strength of F2F than Cl2Cl bonds; it will become apparent that electron-pair repulsions are very important in fluorocarbon chemistry. Overall we can expect profound differences between hydrocarbon and fluorocarbon systems arising from, in particular: (a) electronegativity differences, (b) the existence of unshared electron pairs associated with fluorine, (c) the tendency for displacement of fluorine as F
from unsaturated fluorocarbons, (d) the higher bond strength of C2F than C2H and, to a lesser extent, (e) the larger size of fluorine than hydrogen [107]. Differences between fluorocarbon and chlorocarbon systems are likely to be influenced by (a) the larger steric requirements of chlorine, (b) the lower bond strength of C2Cl than C2F, and (c) the greater availability of 3d orbitals of chlorine. We can now outline, in a collective fashion, some electronic effects of fluorine that act, or have been suggested to act, in a fluorocarbon system but no attempt is made to discuss the detail of these effects at this point.

A Saturated systems (1)

Inductive (through s-bonds) and field (through space) effects arise from a highly polar bond (
Is ), resulting in electron withdrawal to fluorine (Figure 1.11). d+

d

C

F

Figure 1.11

(2)

‘Double bond–no bond resonance’ (and equivalent molecular orbital descriptions) has been suggested to be involved (
R) (Figure 1.12). F

C

F

F

C

F

Figure 1.12

This may be described in molecular orbital terms as interaction of s-electrons in C2F with low-lying s -orbitals in the other C2F bonds.

B Unsaturated systems (1) (2)

Inductive (
Is ) effects act as in saturated systems. Inductive and field effects result in the polarisation of p-electrons (
Ip ) (Figure 1.13). F

Figure 1.13

d- d+ C C

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General Discussion of Organic Fluorine Chemistry

(3)

15

Coulombic or Pauli repulsion occurs between electron pairs on fluorine and p-electrons (þIp ) (Figure 1.14). F

δ+ δ− C C

Figure 1.14

Thus, there is a dichotomy in behaviour of fluorine because effects 1 and 2 lead to electron withdrawal whereas 3 leads to return of electron density from fluorine. (4)

‘No-bond resonance’ (
R) is illustrated in Figure 1.15. CF3

F C ⫽C

C⫽C

F

C

F

Figure 1.15

C

Positively charged species

(1)

Inductive electron withdrawal (
Is ) would tend to destabilise a carbocation (Figure 1.16). F

C 1.16A

C

F

C 1.16B

Figure 1.16

(2)

Mesomeric interaction (þM) of an unshared pair with the empty orbital on carbon, if operating, would lead to stabilisation (Figure 1.17). + C

F

C

+ F

1.17A

Figure 1.17

Later discussion will show that fluorine directly attached to a carbocation centre, as in 1.16A and 1.17A, overall is clearly a stabilising influence, but the effect of fluorine more remote from the centre, as in 1.16B, is strongly destabilising.

D

Negatively charged species

(1)

Inductive electron withdrawal (
Is ) would lead to stabilisation (Figure 1.18). F

C 1.18A

Figure 1.18

C

C

1.18B

F

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16

(2)

Chapter 1

Repulsion between adjacent electron pairs (þIp ) would be destabilising (Figure 1.19). C

F

1.19A

Figure 1.19

It will become apparent that fluorine not directly attached to the carbanionic carbon 1.18B is strongly stabilising but, when directly attached as in 1.18A and 1.19A, it has either a moderate stabilising effect compared with hydrogen, or it definitely destabilises, depending on the stereochemistry of the carbanion. (3)

A ‘negative hyperconjugation’ has been proposed (Figure 1.20). F C

C

C⫽C

F

F F F

F

Figure 1.20

Again, in MO terms, this would be described as interaction of the filled p-orbital on carbon with s -orbitals associated with C2F bonds.

E

Free radicals

(1)

Inductive electron withdrawal (
Is ) will affect the polar characteristics, and hence reactivity, of a radical (Figure 1.21). d+ C

dF

Figure 1.21

(2)

All substituents replacing hydrogen should lower the potential energy of a free radical; this may be represented as a resonance stabilisation (Figure 1.22). C

F

C

F

Figure 1.22

Even from the foregoing crude but useful generalisations, it will be appreciated how unusual the chemistry of fluorocarbon compounds is.

IV

NOMENCLATURE [108, 109]

The nomenclature of fluorocarbon derivatives is based on regarding them as derivatives of the corresponding hydrocarbon compounds.

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General Discussion of Organic Fluorine Chemistry

A

17

Systems of nomenclature

The number of fluorine atoms is indicated in the name and the positions are indicated by numerals or Greek letters according to normal conventions, for example as in Figure 1.23. F

F

F

F

CF3 O CF3 Hexafluoroacetone

1,1,4,4-Tetrafluorocyclohexane

Figure 1.23

To avoid cumbersome use of numbers, when the number of hydrogen atoms in a molecule is four or less and the ratio of hydrogen to halogen atoms is not more than 1:3, then the position of the hydrogen atoms is designated, for example, as in Figure 1.24. CF3CFHCF3

2H-heptafluoropropane

CHClFCF2CF3

1H-1-chlorohexafluoropropane

Figure 1.24

Another system frequently used involves adding a prefix ‘perfluoro’ before the name of the corresponding hydrocarbon analogue. This indicates that all hydrogen atoms that are not part of a recognised functional group are replaced by fluorine, for example as in Figure 1.25. CF3 F

(CF3)3C-OH

F N

Perfluorocyclobutane

Perfluoro-t-butanol

Perfluoro(4-methylpyridine)

Figure 1.25

For cyclic systems, a capital F in the centre of the ring is used frequently to denote that all unmarked bonds are to fluorine, for example as in Figure 1.26. F

Perfluorocyclohexane

Figure 1.26

There are ambiguities and limitations to the use of the ‘perfluoro’ prefix; it should not be used for some substituted derivatives, for example see Figure 1.27. Cl F

1,2-dichlorohexafluorocyclobutane Cl

Figure 1.27

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18

Chapter 1

A simple method for indicating the geometry of stereoisomers is indicated in Figure 1.28. H F

H F

H 1H, 2H / - perfluorocyclohexane

H 1H, / 2H - perfluorocyclohexane

Figure 1.28

For highly fluorinated systems the ‘perfluoro’ system is often much less cumbersome and immediately more meaningful than the numerical system and, for this reason, it will often be used in this book. Both systems can be used, together with parentheses, to refer to individual groups (Figure 1.29). C6H5CF2CF2CF2CF2CF3

(Perfluoro-n-pentyl)benzene

C6H5CF2CF2CFHCF2CF3

(3H-decafluoro-n-pentyl)benzene

Figure 1.29

In many cases, the abbreviations RF and ArF are used to represent perfluoroalkyl and perfluoroaryl groups respectively. A further system of nomenclature has been authorised by the ACS, whereby a capital F preceding the name of a substrate indicates perfluorination, for example as in Figure 1.30. CF3CF2COOH

F-propanoic acid

F

F-benzene

Figure 1.30

B Haloalkanes [109] A perverse system of nomenclature exists for the CFC, HCFC and HFC groups of compounds and, whatever objections to it may be made, it seems to be here to stay. Therefore, to avoid much frustration it is advisable to become acquainted with the rules. A series of three numbers are used (or two if the first is zero) that indicate, in order, the following: Number of carbon atoms minus one (C
1) Number of hydrogen atoms plus one (H þ 1) Number of fluorine atoms (F) Chlorine atoms are not included and, for bromine derivatives, B is added, followed by the number of bromine atoms. Also, a cyclic system has the numbers prefixed by C, for example: Tetrachlorodifluoroethane C2 Cl4 F2 112 Trichlorofluoromethane CCl3 F 11 Perfluorocyclobutane C4 F8 C318 Dibromodifluoromethane CBr2 F2 12B2

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General Discussion of Organic Fluorine Chemistry

19

For positional isomers, the deviation from symmetrical fluorine substitution is denoted by a letter, for example: CF2 H2CF2 H 134 CF3 2CFH2 134a

REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

D.B. Harper and D. O’Hagan, Nat. Prod. Rep., 1994, 11, 123. D.B. Harper and D. O’Hagan, J. Fluorine Chem., 2000, 100, 127. R.D. Chambers, Fluorine in Organic Chemistry, John Wiley and Sons, New York, 1973. M. Stacey, J.C. Tatlow, A.G. Sharpe, et al. (eds), Advances in Fluorine Chemistry, Vols 1–7, Butterworth, London, 1960–1973. P. Tarrant (ed.), Fluorine Chemistry Reviews, Vols 1–8, Dekker, New York, 1967–1977. M. Howe-Grant (ed.), Kirk-Othmer Encyclopedia of Chemical Technology, 4th edition, Vol. 11, Organic Fluorine Compounds, John Wiley and Sons, New York, 1994. M. Howe-Grant (ed.), Fluorine Chemistry: A Comprehensive Treatment, John Wiley and Sons, New York, 1995. A.E. Pavlath and A.L. Leffler, Aromatic Fluorine Compounds, Reinhold, New York, 1962. A.J. Rudge, The Manufacture and Use of Fluorine and its Compounds, Oxford University Press, London, 1962. W.A. Sheppard and C.M. Sharts, Organic Fluorine Chemistry, Benjamin, New York, 1969. S. Patai (ed.), The Chemistry of the Carbon–Halogen Bond, John Wiley and Sons, London, 1973. L.A. Wall, Fluoropolymers, Wiley-Interscience, New York, 1973. R. Filler, Biochemistry Involving Carbon–Fluorine Bonds, American Chemical Society, Washington DC, 1976. J.W. Root, Fluorine-containing Free Radicals, American Chemical Society, Washington DC, 1978. R.D. Chambers and S.R. James in Halo Compounds, ed. J.F. Stoddart, Pergamon, Oxford, 1979, p. 493. R. Filler and Y. Kobayashi (eds), Biomedical Aspects of Fluorine Chemistry, Elsevier Biomedical Press, Amsterdam, 1982. R. E. Banks (ed.), Preparation, Properties and Industrial Applications of Organofluorine Compounds, Ellis Horwood, Chichester, 1982. I.L. Knunyants and G.G. Yakobson, Synthesis of Fluoro-organic Compounds, Springer-Verlag, Berlin, 1985. B.E. Smart in Fluorinated Organic Molecules, ed. J.F. Liebman and A. Greenberg, VCH Publishers, Deerfield Beach, 1986, p. 141. R.E. Banks, D.W.A. Sharp and J.C. Tatlow (eds), Fluorine: The First One Hundred Years, Elsevier Sequoia, New York, 1986. J.F. Liebman, A. Greenberg and W.R. Dolbier (eds), Fluorine Containing Molecules, Structure, Reactivity, Synthesis and Applications, VCH Publishers, New York, 1988. N.F. Taylor (ed.), Fluorinated Carbohydrates: Chemical and Biochemical Aspects, American Chemical Society, Washington DC, 1988. L. German and S. Zemskov (eds), New Fluorinating Agents in Organic Synthesis, SpringerVerlag, Berlin, 1989. J.T. Welch and S. Eswarakrishnan, Fluorine in Bioorganic Chemistry, John Wiley and Sons, New York, 1991. J.T. Welch (ed.), Selective Fluorination in Organic and Bioorganic Chemistry, American Chemical Society, Washington, DC, 1991. K.L. Kirk, Biochemistry of Halogenated Organic Compounds, Plenum, New York, 1991.

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20

Chapter 1

27 G.A. Olah, R.D. Chambers and G.K.S. Prakash (eds), Synthetic Fluorine Chemistry, Wiley-Interscience, New York, 1992. 28 M. Hudlicky, Chemistry of Organic Fluorine Compounds, 2nd revised edition, Ellis Horwood, Chichester, 1992. 29 R.E. Banks, B.E. Smart and J.C. Tatlow (eds), Organofluorine Chemistry. Principles and Commercial Applications, Plenum, New York, 1994. 30 T. Hayashi and V.A. Soloshonok, Tetrahedron: Asymm., 1994, 5, 955. 31 V.P. Kukhar and V.A. Soloshonok, Fluorine-containing Amino Acids, John Wiley and Sons, New York, 1995. 32 M. Hudlicky and A.E. Pavlath (eds), Chemistry of Organic Fluorine Compounds II, American Chemical Society, Washington DC, 1995. 33 T.L. Gilchrist (ed.), Comprehensive Organic Functional Group Transformations, Vol. 6, Elsevier Science, Oxford, 1995. 34 B.E. Smart, Chem. Rev., 1996, 96, 1555. 35 G. Resnati and V.A. Soloshonok, Tetrahedron, 1996, 52, 1. 36 B. Baasner, H. Hegemann and J.C. Tatlow (eds), Houben-Weyl: Methods of Organic Chemistry, Vols E10a–E10c, Organo-fluorine Compounds, Georg Thieme, Stuttgart, 1999. 37 J.H. Clark, D. Wails, and T.W. Bastock, Aromatic Fluorination, CRC Press, Boca Raton, 1996. 38 R.D. Chambers (ed.), Organofluorine Chemistry. Fluorinated Alkenes and Reactive Intermediates, Springer-Verlag, Berlin, 1997. 39 R.D. Chambers (ed.), Organofluorine Chemistry: Techniques and Synthons, Springer-Verlag, Berlin, 1997. 40 W.S. Brey and M.L. Brey in Fluorine-19 NMR, ed. D.M. Grant and R.K. Harris, John Wiley and Sons, New York, 1996, p. 2063. 41 M.R. Kilbourn, Fluorine-18 Labeling of Radiopharmaceuticals, National Academy Press, Washington DC, 1990. 42 O. Matsson, S. Axelsson, A. Hussenius and P. Ryberg, Acta. Chem. Scand., 1999, 53, 670. 43 H. Moissan, Compt. Rend., 1890, 110, 276. 44 H. Moissan, Le Fluor et ses Compose´s, Steinheil, Paris, 1900. 45 F. Swarts, Bull. Acad. Roy. Belg., 1892, 24, 474. 46 T. Midgley and A.L. Henne, Ind. Eng. Chem., 1930, 22, 542. 47 P. Lebeau and A. Damiens, Compt. Rend., 1926, 182, 1340. 48 P. Lebeau and A. Damiens, Compt. Rend., 1930, 191, 939. 49 O. Ruff and R. Keim, Z. Anorg. Allg. Chem., 1930, 192, 249. 50 F. Swarts, Bull. Acad. Roy. Belg., 1922, 8, 343. 51 F. Swarts, Bull. Acad. Roy. Belg., 1931, 17, 27. 52 J.H. Simons and L.P. Block, J. Am. Chem. Soc., 1937, 59, 1407. 53 J.H. Simons (ed.), Fluorine Chemistry, Vol. 1, Academic Press, New York, 1950. 54 J.H. Simons (ed.), Fluorine Chemistry, Vol. 2, Academic Press, New York, 1954. 55 C. Slesser and S.R. Schram (eds), Preparation, Properties and Technology of Fluorine and Organic Fluoro Compounds, McGraw-Hill, New York, 1951. 56 O. Ruff and O. Bretschneider, Z. Anorg. Allg. Chem., 1933, 210, 173. 57 E.G. Locke, W.R. Brode and A.L. Henne, J. Am. Chem. Soc., 1934, 56, 1726. 58 R.J. Plunkett, US Pat. 2 230 654 (1941); Chem. Abstr., 1941, 35, 3365. 59 H. Schofield, J. Fluorine Chem., 1999, 100, 7. 60 S. Rozen in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and G.K.S. Prakash, John Wiley, New York, 1992, p. 143. 61 R.E. Banks and K.C. Lowe, Fluorine in Medicine in the 21st Century, UMIST Chemserve, Manchester, 1994. 62 R.E. Banks, Fluorine in Agriculture, Fluorine Technology Ltd, Manchester, 1994. 63 R.E. Banks, Fluorocarbons and their Derivatives, MacDonald, London, 1970.

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General Discussion of Organic Fluorine Chemistry

64 65 66 67 68 69 70 71 72 73 73a 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97

21

R.L. Powell in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 59. M. Silvester, Speciality Chemicals, 1991, 392. M.J. Molina, Angew. Chem., Int. Ed. Engl., 1996, 35, 1778. F.S. Rowland, Angew. Chem., Int. Ed. Engl., 1996, 35, 1786. C.S. Todd, The Use of Halons in the United Kingdom and the Scope for Substitution, HMSO, London, 1991. R.E. Banks, J. Fluorine Chem., 1994, 67, 193. L.C. Clark and F. Gollan, Science, 1966, 152, 1755. J.G. Riess, Chem. Rev., 2001, 101, 2797. R.M. Flynn in Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 11, ed. M. HoweGrant, John Wiley and Sons, New York, 1994, p. 525. R.J. Lagow, T.R. Bierschenk, T.J. Juhlke and H. Kawa in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and G.K.S. Prakash, John Wiley and Sons, New York, 1992, p. 97. G. Hougham (ed.) Fluoropolymers, Academic/Plenum Publishers, New York, 1999. D.P. Carlson and W. Schmeigel in Ullmanns Encyclopedia of Industrial Chemistry, Vol. A11, VCH Publishers, Weinheim, 1988, p. 393. R.F. Brady, Chem. Britain, 1990, 26, 427. C.A. Sperati in Properties of Fluoropolymers, ed. J. Brandrup and E.H. Immergut, Wiley, New York, 1975. A. Eisenberg and H.L. Yeager, Perfluorinated Ionomer Membranes, American Chemical Society, Washington DC, 1982. V.A. Soloshonok (ed.), Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, John Wiley and Sons, New York, 1999. M. Schlosser in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 613. D.F. Halpern in Anaesthetics Review, ed. R.E. Banks and K.C. Lowe, UMIST Chemserve, Manchester, 1994, Paper 15. B.E. Smart, J. Fluorine Chem., 2001, 109, 3. D. O’Hagan and H.S. Rzepa, J. Chem. Soc., Chem. Commun., 1997, 645. D. Seebach, Angew. Chem., Int. Ed. Engl., 1990, 29, 1320. M.R. Kilbourn in Fluorine-18 in Nuclear Medicine, ed. R.E. Banks, UMIST Chemserve, Manchester, 1994. S.B. Walker, Fluorine Compounds as Agrochemicals, Fluorochem Ltd, Glossop, 1989. S.R.A. Peters and R.J. Hall, J. Biochem. Pharmacol., 1959, 2, 25. D. O’Hagan and D.B. Harper, Nat. Prod. Rep., 1994, 11, 123. D. O’Hagan, C. Schaffrath, S.L. Cobb, J.T.G. Hamilton and C.D. Murphy, Nature, 2002, 416, 279. T. Kitazume and T. Yamazaki in Organofluorine Chemistry. Techniques and Synthons, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 91. T. Fujisawa and M. Shimizu in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 307. T.F. Herpin, W.B. Motherwell and M.J. Tozer, Tetrahedron: Asymm., 1994, 5, 2265. D.M. LeGrand and S.M. Roberts, J. Chem. Soc., Chem. Commun., 1993, 1284. D.B. Berkowitz and M. Bose, J. Fluorine Chem., 2001, 112, 13. S. Cesaro-Tadic, D. Lagos, A. Honegger, J.H. Rickard, L.J. Partridge, G.M. Blackburn and A. Pluecktun, Nat. Biotechnol., 2003, 21, 679. B. Novo and G. Resnati in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 349. K. Uneyama in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 391. C.R.S. Briggs, D. O’Hagan, J.A.K. Howard and D. Yufit, J. Fluorine Chem., 2003, 119, 9.

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22

Chapter 1

98 99 100 101 102

K. Shinoda, M. Hato and T. Hayaski, J. Phys. Chem., 1972, 76, 909. H. Kuneida and K. Shinoda, J. Phys. Chem., 1976, 80, 2468. W. Guo, T.A. Brown and B.M. Fung, J. Phys. Chem., 1991, 95, 1829. J.P. Badyal, Chem. Britain, 2001, 37, 45. R.D. Chambers, C. Magron, G. Sandford, J.A.K. Howard and D.S. Yufit, J. Fluorine Chem., 1999, 97, 69. P. Kirsch and M. Bremer, Angew. Chem., Int. Ed. Engl., 2000, 39, 4216. B.E. Smart in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 57. N.N. Greenwood and A. Earnshaw, Chemistry of the Elements, Pergamon, Oxford, 1989. G.A. Olah, Halonium Ions, Wiley-Interscience, New York, 1975. C.G. Beguin in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 601. R.E. Banks and J.C. Tatlow in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 1. R.E. Banks in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 12.

103 104 105 106 107 108 109

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Chapter 2

Preparation of Highly Fluorinated Compounds

I

INTRODUCTION

Two different approaches have been adopted here in describing fluorination reactions: the production of highly fluorinated systems is discussed in this chapter on the basis of a comparison of methods, whereas selective fluorinations are described in Chapter 3 in terms of the conversion of functional groups. If we wish to produce highly fluorinated systems, then the starting materials are usually hydrocarbons, polychloro compounds or, of course, highly fluorinated ‘building-blocks’ for conversion to other compounds.

A

Source of fluorine

Fluorine is widely distributed in nature [1] and it is estimated that, among the elements, fluorine is about thirteenth in abundance. Phosphate rock, which is processed on a multimillion-ton scale as raw material for the fertiliser industry, contains as much as 3.8% of fluorine and is a very rich source of the element. However, the fluorine recovered from this process as fluorosilicic acid is still not a commercially competitive source of fluorine compared with fluorspar (CaF2 ), although reserves of the latter are said to be limited and it is expected that use of fluoride in phosphate rocks will eventually be increased. For industry, the source of fluorine is essentially anhydrous hydrogen fluoride [2], which is made commercially by distillation (b.p. 19.58 C) from a mixture of fluorspar and concentrated sulphuric acid. The liquid fumes in air and great care must be taken to avoid its contact with the skin, otherwise unpleasant burns are obtained which are difficult to heal and often require a subcutaneous injection of calcium gluconate [3, 4]. Synthesis of highly fluorinated compounds, starting from hydrogen fluoride, is therefore achieved by a variety of techniques: directly by reaction of an organic compound with hydrogen fluoride or by electrolysing solutions of certain compounds in HF, or indirectly by reactions with elemental fluorine or with metallic fluorides (Figure 2.1).

II

FLUORINATION WITH METAL FLUORIDES [5]

There is a considerable literature [6–8] on this group of reactions, embracing an extremely wide variety of experimental conditions, and the patent literature abounds with reports of different ‘catalyst’ systems. It is possible to group some of these reactions partly on a basis of mechanism if some rather broad generalisations are made about the mechanistic pathways. The aim here is to assist in the choice of the type of reagent but it is not Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

23

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 24

24

Chapter 2 H2SO4

CaF2

KF.2HF

anhydrous HF

F2

m.p. ca. 100
C

Metal Fluorides

Transition Metal Fluorides

Figure 2.1

intended to imply that detailed mechanisms are understood, nor should the classifications be regarded as rigid. There are three main groups, as described below.

A Swarts reaction and related processes (halogen exchange using HF) These reactions are based on hydrogen fluoride and involve, essentially, a nucleophilic displacement of halogen (for convenience, in the sense intended throughout this book, this term usually excludes fluorine). However, only the most reactive halides such as allylic and benzylic ones can be fluorinated by anhydrous HF alone [9] (Figure 2.2). HF, 40
C

PhCCl3

PhCF3

HF, rt Ph3CCl

70%

½9


62%

Ph3CF

CF3

CCl3 HF, catalyst Cl

300−500
C

N

80% Cl

N

Figure 2.2

Hydrogen fluoride acts both as a Friedel–Crafts catalyst and a fluorinating agent in a one-step preparation of trifluoromethylated aromatics [10] (Figure 2.3). +

CCl4

+

HF

CF3

5hr, 100
C

½10
92%

Figure 2.3

Halogen exchange at less activated sites requires a Lewis acid catalyst and an important part of the function of the catalyst, usually a metal fluoride or a chromium species, is to assist the removal of halogen as halide ion. Therefore, these reactions could be considered to involve carbocationic intermediates (Figure 2.4). C

Figure 2.4

Cl

+

MFx

C

MFxCl

F

C

F

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Preparation of Highly Fluorinated Compounds

25

It is more likely, however, that four-centre reactions occur since the metal fluorides can be used either alone or in catalytic amounts in the presence of anhydrous hydrogen fluoride. This latter process was developed by Swarts and it now usually bears his name (Figure 2.5). Cl C

Cl

+

MFx

δ− MFx-1

δ+ C

F C

F

F

Figure 2.5

Generally, reactions performed in the liquid phase utilise hydrogen fluoride in combination with antimony fluoride catalysts and their efficiency stems from the greater strength of the bond from antimony to chlorine than to fluorine. Pentavalent antimony catalysts, such as SbF5 and SbF3 Cl2 , are more efficient than trivalent species because they are extremely strong Lewis acids. Carbocations are formed in the presence of antimony pentahalides and, indeed, one of the now-classic techniques developed by Olah and his co-workers for the generation of relatively stable carbocations involves the reaction of an organic halide with antimony pentafluoride, in solvents such as sulphur dioxide, at low temperature [11]. On the industrial scale, reactions are performed in the vapour phase and chromium(III)-based catalysts are extensively used in the production of hydrofluorocarbons (HFCs). In general, in this group of fluorination reactions, reactivities of the substrates and the nature of the products obtained can be accounted for in terms of the corresponding carbocation intermediates.

1

Haloalkanes

For many years chlorofluorocarbons (CFCs) were manufactured in huge quantities by Swarts-type processes but, after the introduction of the Montreal Protocol legislation, these compounds were superseded by non-ozone depleting HFCs (see Chapter 1). Fortunately, much of the chemistry developed for the manufacture of the CFCs can be adapted for the production of HFCs [7, 12–15]. Generally, conversion of 2CCl3 groups to 2CFCl2 can be easily accomplished, reflecting both the stabilisation of the intermediate carbocations by chlorine and the relief in steric strain associated with replacement of chlorine by fluorine. Further fluorination of the 2CFCl2 group is possible but becomes progressively more difficult [3] due to the decrease in the donating ability of the chlorine. Fluorination of 2CFCl2 groups can also be achieved but RF CH2 Cl moieties (where RF ¼ perfluoroalkyl) are generally very difficult to fluorinate due to the lower stability of the derived carbocation intermediates. These effects can all be seen in the two most important industrial routes to HFC-134a, now a leading refrigerant, in which chromium(III) catalysts are used in conjunction with HF for the halogen exchange steps [15] (Figure 2.6).

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 26

26

Chapter 2 CCl2=CHCl

HF

HF

CF2ClCClH2

Cr(III)

CF3CH2Cl

Cr(III)

½15


HF

CF3CH2F HFC 134a

CCl3-CCl3

AlCl3

HF CF2ClCFCl2

Cr(III)

CF3CCl3 Cr(III) HF H2 / Pd

CF3CH2F

CF3CFCl2

HFC 134a

Figure 2.6

2 Influence of substituent groups Groups such as alkyl [16] and aryl [17], double bonds [18], oxygen [19] and sulphur [20] (that are known to stabilise carbocations), when attached to the carbon centres that are undergoing halogen exchange, activate the process (Figure 2.7). i

PhCCl2CCl3

i, SbF3 / SbCl5, 150
C i

CCl2CClCCl3

+

PhCF2CCl3

PhCFClCCl3 6%

60%

CF3CClCCl2

+

CF2ClCClCCl2

43%

i, SbF3, 150
C i

CH3CCl2CH3

CH3CF2CH3

½17


½18


28%

+

CH3CFClCH3

½16


10%

85% i, SbF3 / SbCl5, rt i CCl3CCl2OCH3

CCl3CF2OCH3

84%

½19


i, SbF3, reflux

CCl3SCH3

i

i, SbF3 / SbCl5, 90
C

Figure 2.7

CF3−S−CH3

73%

½20


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Preparation of Highly Fluorinated Compounds

27

In reactions with hexachlorobutadiene, 1,4-addition of chlorine precedes fluorination and the product arises from exchange at the two reactive allylic trihalomethyl groups [21]. Perchlorocyclopentene [22] and hexachlorobenzene [23] are also extensively fluorinated by this procedure (Figure 2.8). SbF3Cl2

Cl2CCClCCl=CCl2

CCl3CClCClCCl3

CF3CClCClCF3

CF3CClCFCF3

+

SbF3, SbF3Cl2

Cl

½21


Cl

F

½22


72% Cl

Cl SbF5, 160
C

Cl

F

Cl

Cl

½23


F

+ Cl

Cl

30%

20%

Figure 2.8

The fluorination of hexachloroacetone by HF over chromia catalysts at high temperature is an efficient process for the synthesis of hexafluoroacetone [20] (Figure 2.9). O

O HF, 350
C Cl3C

CCl3

Chromia cat.

½20
F3C

CF3

Figure 2.9

In addition to the antimony fluorides, silver, mercury, thallium, aluminium, zinc, zirconium, chromium and other fluorides [7] such as mercury(II) fluoride, vanadium pentafluoride [24] and various transition metal oxide fluorides [25] have been used in exchange processes, although much less widely.

B

Alkali metal fluorides (see also Chapter 3, Section IIB) [26]

This second group of reactions is related to the first in that nucleophilic displacement of a halide ion is involved, but here Lewis acid assistance by the metal fluoride is not a prime factor. Therefore, ionic fluorides are applicable where an unassisted nucleophilic displacement process is feasible, even if forcing conditions are necessary (Figure 2.10).

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 28

28

Chapter 2 F F

Cl

C

C

C

C

F

C

C

+

Cl

Cl

Figure 2.10

1 Source of fluoride ion ˚ , respectively [27]) Fluoride ion is much smaller than chloride (ionic radii 1.47 and 1.75 A 1 and the heat of hydration of fluoride is about 134 kJmol greater than chloride. The order of nucleophilic strength of halide ions in aqueous solution is I  Br > Cl > F , which is the opposite of the order of strengths of the bonds of the halogens to carbon. Therefore, the order of reactivity is a consequence of the greater difficulty in disturbing the hydration sphere of the smaller ions. The same order seems to be observed in most hydrogen-bonding solvents but, in dipolar aprotic solvents, the order follows that of increasing halogen bond strength to carbon, that is F > Cl > Br  I [28]. Consequently, in order to reduce hydrogen bonding between the fluoride ion source and the solvent, and hence to increase the nucleophilic strength of fluoride, reactions are generally carried out using polar, aprotic media [29, 30] such as acetonitrile, sulpholane, N-methylpyrollidinone or glymes. These solvents dissolve sufficient metal fluoride, due to coordination of the oxygen or nitrogen donor groups present with the metal cation, and presumably the fluoride ion remains relatively unsolvated. These fluorinations are not simply solution-phase processes, because some reaction undoubtedly occurs on the surface; indeed, the surface area of the metal fluoride is extremely important to reactivity and in some cases it has been demonstrated that the amount of solid metal fluoride is important [31]. Also, in some circumstances the alkali metal fluorides can be used most effectively without a solvent [32, 33], and in these cases it is likely that an MF/MCl melt is produced as the reaction proceeds. Fluoride ion is a relatively strong base which has been used to effect a large number of base-catalysed reactions in general organic synthesis [34, 35] and so, if forcing conditions are required for a particular halogen exchange reaction, the limiting feature can be proton abstraction by fluoride ion from the solvent or the substrate. Because of the low solubility of metal fluorides in even very polar aprotic solvents, high temperatures are generally required; this restricts the use of alkali metal fluorides to relatively simple substrates. Consequently, development of more reactive forms of fluoride ion, which may be useful for introduction of fluorine into more complex molecules, is an area of continuing interest [36, 37]. Methods of activating metal fluorides (usually potassium fluoride) fall into two broad classes: (a) increasing the surface area of the metal fluoride by spray drying [38, 39], freeze drying [40], recrystallising from methanol [41] or absorbing onto a solid inert support such as calcium fluoride [42], alumina [43], graphite [44] or a polymer [45]; or, (b) increasing the solubility of the metal fluoride in aprotic solvents by the addition of coordinating crown ethers [46, 47] such as 18-crown-6 or a phase-transfer catalyst such as tetraphenylphosphonium bromide [48, 49] or a tetra-alkylammonium salt [50]. A search for other more soluble sources of nucleophilic fluoride continues and reagents such as tetra-alkylammonium fluorides [51, 52], various amine hydrofluorides [53, 54], diethylaminosulphur trifluoride [55] (DAST), tetrabutylammonium (triphenylsilyl)difluorosili-

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Preparation of Highly Fluorinated Compounds

29

cate [56] and tris(dimethylamino)sulphonium difluorotrimethylsiliconate [57] (TAS-F) have been used for the selective introduction of fluorine into organic substrates with varying degrees of success. However, in soluble reagents such as Me4 NF and other socalled ‘naked fluoride’ systems, the fluoride ion is so exceptionally reactive that competing proton abstraction from the solvent, such as acetonitrile, or halogen exchange with a chlorinated solvent takes place [51, 58]. Consequently, in the development of new fluoride-ion reagents, a balance must be achieved between having sufficiently high fluoride nucleophilicity to effect halogen exchange and, at the same time, sufficiently low fluoride-ion basicity to prevent unwanted side reactions. Indeed, it has been reported that hydrated tetrabutylammonium fluoride is beneficial in reducing elimination products in reactions with 1-bromo-octane [52] (Figure 2.11). Bu4NF

+ 10H2O

+

80
C

C8H17Br

C8H17F CH3CN

+

CH2CH-C6H13

91%

½52


9%

Figure 2.11

Under most aprotic conditions a general order of reactivity of the alkali-metal fluorides is CsF > KF > NaF, LiF; that is, the fluoride with the lowest lattice energy is the most efficient fluorinating agent. This highlights the over-simplification of ignoring the role of the counter-ion in nucleophilic displacement of halide by fluoride ion. In reactions that do not involve a solvent, the lattice energy itself will be an especially important factor in the process, as for example in Figure 2.12. When the metal M is large, the lattice energy difference between the halides is most favourable for the exchange reaction [59]. MF

+

C

Cl

MCl

+

C

F

Figure 2.12

A general process that involves direct and efficient reaction of fluorspar with organic halides would be very desirable but, so far, this has not been realised, except through generation in situ of hydrogen fluoride [60].

2

Displacements at saturated carbon

Displacement of halide by fluoride ion from alkyl halides usually occurs by an SN 2 process with inversion of configuration [37], and since it is well known that nucleophilic displacement of chloride from polychloroalkanes becomes progressively more difficult with increasing chlorine content, it is hardly surprising that highly fluorinated alkanes are not generally synthesised by this method. However, in favourable cases more than one fluorine atom can be introduced; some examples illustrating different conditions used in ‘Halex’ processes are given in Table 2.1. Other selective nucleophilic fluorinations are discussed later (Chapter 3, Section II).

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 30

30

Chapter 2

Fluorinations with alkali-metal fluorides

Table 2.1 Compound

Conditions

Products

C6 H13 Cl CH2 Cl2 CHCl2 COOCH3 CH3 (CH2 )7 Br CCl3 CCl2 CCl3

KF; (CH2 OH)2 ;(HOCH2 CH2 )2 O; 175–1858 C KF, HF, 3008 C KF, 220–2308 C KF, 18-crown-6, MeCN KF, 1908 C N-Methyl-2-pyrrolidone

C6 H13 F CH2 F2 CHF2 COOCH3 CH3 (CH2 )7 F CF3 CCl2 CF3

Cl

KF, 4808 C, autoclave, no solvent

N

Yield (%) Ref. 54 82 18 92  60

[61] [62] [63] [46] [64]

Cl F

F

N

N

[32]

3 Displacements involving unsaturated carbon Alkene derivatives: There are three processes that can lead to nucleophilic displacement of halide by fluoride ion in unsaturated systems (Figure 2.13). 1.

Addition / Elimination X

F

+ X

+ X

2.

F

F

Allylic or Benzylic Substitution

X F

F + X

3.

Nucleophilic Substitution with Rearrangement, SN2'

F F

+ X

X

Figure 2.13

Displacement of halide by fluoride

Only perfluorocyclopentene has been synthesised directly by this route; it can be seen that, here, allylic rearrangements can occur to make all positions potentially vinylic and therefore reactive [64]. An analogous situation applies to hexachlorobutadiene. These reactions may also be carried out with potassium fluoride that has been exposed to Sulpholan or 18-crown6, but then suspended in a fluorocarbon. Under these conditions, a significant proportion of hexafluoro-2-butyne is formed, presumably because the latter is extracted into the fluorocarbon, pre-empting further reaction with fluoride [65] (Figure 2.14).

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 31

Preparation of Highly Fluorinated Compounds KF, NMP, 200
C

Cl NMP

31

F

= N-methyl-2-Pyrrolidone

Cl F Cl

etc.

Cl

Cl

F

½65


Cl F

F

CFCl2−CHClCCl=CCl2

CF3CH=CFCF3

KF / NMP

CCl2=CClCCl=CCl2 KF/Sulpholan, Perfluorocarbon CF3CH=CFCF3 25%

CF3C

CF3 75%

Figure 2.14

Aromatic compounds: Nucleophilic displacement of halide ion from haloaromatic compounds containing other electronegative substituents is well known; this process has been widely exploited for the synthesis of fluorinated aromatic compounds (Table 2.1) and is discussed later (see Chapter 9, Section II).

C

High-valency metal fluorides

This group of reactions [66, 67] is distinguished from those discussed earlier on the basis that the previous examples involve overall nucleophilic displacement reactions of groups (mainly other halogen) by fluoride, frequently with some degree of assistance for the leaving group by the metal. However, with the present group, the process involves change of a higher-valency metal fluoride to a lower-valency state, and therefore the metal acts somewhat like a fluorine carrier, although it is emphasised that these reactions do not involve the formation and reaction of elemental fluorine (Figure 2.15). The high-valency metal fluorides, mainly cobalt trifluoride, bring about extensive fluorination: hydrogen is replaced by fluorine and saturation of double bonds and aromatic systems usually takes place, while chlorine is frequently retained. There is much less fragmentation during this process than during direct fluorination by elemental fluorine, because the heat of reaction with cobalt trifluoride is approximately half that of the corresponding direct fluorination process [68] (Figure 2.16).

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 32

32

Chapter 2

C

C

+

H

2MFn

+

C

C

2MFn

+

F

C

C

F

F

HF

+

+

2MFn-1

2MFn-1

Figure 2.15

2 CoF2

C

Figure 2.16

H

+

2 CoF3 , ∆H (250
C)

F2

+

2 CoF3

C

F

= −234kJmol−1

+ HF +

½68


2 CoF2

DH is ca  209 to 230 compared with ca 426 to 435 kJmol-1 for direct fluorination

The most important member of this group is cobalt trifluoride; the present discussion will be essentially limited to the use of this fluorinating agent, although use of a variety of other fluorides has been reported, with varying degrees of success [66, 67]. Other related high-valency metal salts such as the tetrafluorocobaltates of potassium [69, 70] and caesium [71], KAgF4 [72] and K2 NiF6 [73] (compare also NiF3, Section III) are milder fluorinating agents for aromatic systems. It is also worthwhile to re-emphasise that the classifications presented here must not be regarded as rigid because, for example, antimony pentafluoride has characteristics that really span both groups. It is now reasonably well established that cobalt trifluoride fluorinations proceed via a one-electron transfer oxidative process [74, 75] as outlined in Figure 2.17. R-H +

RH

−H +

CoF3

R

RF

½74; 75


CoF3 CoF2 + F

R'F

CoF3

R'

rearrange

R

F

RF

Figure 2.17

The presence of carbocationic intermediates was inferred from the isolation of other perfluorinated isomers formed via rearrangement upon fluorination of n-hexane [75]. Similar arguments have been suggested for fluorinations of aromatics [74, 76, 77], ethers [78] and amines [79].

1 Cobalt trifluoride and metal tetrafluorocobaltates Laboratory-scale fluorinations with cobalt trifluoride most commonly utilise the technique pioneered by Fowler and his co-workers [80] whereby cobalt trifluoride is formed,

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Preparation of Highly Fluorinated Compounds

33

and subsequently regenerated, by passing fluorine over the difluoride under agitation. The substrate is then added in the vapour phase, in a stream of nitrogen usually at high temperatures (300–4008 C). Industrial processes [81], such as that used by F2 Chemicals Ltd for the production of a range of perfluorocarbon fluids (Flutect), are operated on a continuous process in which both fluorine and the hydrocarbon are fed simultaneously into the reactor, enabling fluorination and regeneration of the trifluoride to occur. This method is probably the best available for general synthesis of saturated fluorocarbons and both open-chain and cyclic fluorocarbons have been produced readily from appropriate aliphatic or aromatic hydrocarbons, yields usually being quite high (Table 2.2). Formation of perfluorinated ethers by cobalt trifluoride is generally a low-yielding process, because of fragmentation and partial fluorination. However, incorporation into the substrate of electron-withdrawing polyfluoroalkyl groups moderates the fluorination and allows high yields to be obtained [78]. Table 2.2 Fluorinations using cobalt trifluoride Starting material n-C5 H12

Conditions (8 C)

Product

Yield (%)

Ref.

275–325

n-C5 F12

67%

[80]

85%

[82]

C2H5

C2F5

350 F

350

F

[83]

F

350

[84] F N

N

350

Cl

C6 F12n Cln

O

III

N

CH3

70%

O

[78]

CF2CF2CF3

O

100

[85]

F

440 CF2CFHCF3

O

F

F

N

CF3

[86]

ELECTROCHEMICAL FLUORINATION (ECF) [87]

Simons and his co-workers discovered a remarkable fluorination process [88–90] which is still being studied [87, 91–95]. Many organic compounds dissolve readily in anhydrous

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34

Chapter 2

hydrogen fluoride to give conducting solutions and it was found that when a direct electric current was passed through a solution of this type, or through a suspension of a compound in anhydrous hydrogen fluoride to which some electrolyte had been added to give a conducting medium, hydrogen was evolved at the cathode and the organic material was fluorinated. Low voltages are used (usually 5–6 V) so that generation of elemental fluorine is not involved. However, the process is not well understood and suggestions concerning the mechanism broadly fall into two classes [94]. High-valency nickel fluorides formed at the surface of the anode are the most likely fluorinating agents [96], although formation of radical cation intermediates has been suggested [97] (Figure 2.18). R

H

−e

R

−H

H

R

−e

F

R

RF

½97


Figure 2.18

The method is similar to the use of high-valency metal fluorides because it is usual for all the hydrogen in an organic compound to be replaced by fluorine; unsaturated centres, multiple bonds or aromatic systems are saturated but some functional groups are retained, and it is this last feature that makes this method attractive. Unfortunately, however, although many examples are quoted, especially in the patent literature, the yields are frequently difficult to deduce or are very low. This is particularly the case with hydrocarbons and, in general, as the length of the hydrocarbon chain in functional compounds increases, so the yields decrease. Under its present state of development the method is only preparatively useful in limited cases, for example for carboxylic or sulphonic acids, amines and some ethers (see Table 2.3) where the yields are particularly high, or in cases where alternative methods are even more inefficient. The process is in commercial use for the production of a range of perfluorocarbons and perfluoro acids.

Table 2.3 Electrochemical fluorinations Starting material n-C8 H18 (C2 H5 )3 N

N

Product

Yield (%)

Ref.

n-C8 F18 (C2 F5 )3 N

15 þ tar 27

[89] [98]

F

37

[99]

20 þ 2 85 20 96 25

[100] [101] [102] [103] [103]

50

[104]

N

F

F

(CH3 )2 S CH3 COF C7 H15 COCl CH3 SO2 F C8 H17 SO2 Cl

CF3 SF5 þ (CF3 )2 SF4 CF3 COF C7 F15 COF CF3 SO2 F C8 F17 SO2 F F

O

CF2CFHCF3

O

CF2CF2CF3

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Preparation of Highly Fluorinated Compounds

35

Work with pre-formed high-valency nickel fluorides, i.e. NiF3 and NiF4, has demonstrated the very high level of reactivity of such compounds [105–107]. These are the only reagents described so far that will bring about complete fluorination at room temperature or below (Figure 2.19), and therefore mirror ECF procedures. RFH

RFH

O

RFH

= -CF2CFH-CF3

O

C3F7

i

C3F7

F

i, NiF3, anhyd.HF, −28
C to rt, 24hr

Figure 2.19

Clearly these results support the idea of forming higher nickel fluorides at the anode surface during ECF but there is also the possibility that these high-valency systems could be simply regarded as fluorine atom carriers, which would account for the high level of reactivity. For any oxidation process proceeding by the ECB ECN mechanism described in Figure 2.18, it would be expected that fluorination should become progressively more difficult to achieve. However, presentation of a surface of, essentially, fluorine atoms to a substrate would circumvent this difficulty of interpretation. It is worth noting that the nickel fluoride K2 NiF6 [108] decomposes on heating to give elemental fluorine.

IV A

FLUORINATION WITH ELEMENTAL FLUORINE [109] Fluorine generation

Since anhydrous hydrogen fluoride is not sufficiently conducting, fluorine is generated at the anode by electrolysis of KF2HF, which melts conveniently around 1008 C and the cell can therefore be run at a reasonable temperature. Considerable research has been carried out on the design of fluorine cells and this is fully discussed elsewhere [2, 110].

B

Reactions

Reactions between hydrocarbons and elemental fluorine are extremely exothermic because of the high heats of formation of bonds from fluorine to carbon and hydrogen (approximately 456 and 560 kJmol1 , respectively) [27, 111]. The value of DH for the dissociation of fluorine is very low (ca. 157 kJmol1 ), so it is frequently assumed that the preferred fluorination process proceeds by a radical chain mechanism (Figure 2.20), although this may not always be the case. F2 RH R

2F + +

K = 10−20

F

R

+

HF

F2

RF

+

F

Figure 2.20

Fluorinations will proceed in the dark, and the initiation process poses a question. It has been pointed out [112] that, although fluorine is not appreciably dissociated at room

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36

Chapter 2

temperature (F2 ¼ 2F  , K ¼ 1020 ), the low activation energy of the hydrogen abstraction reaction would mean that even this low degree of dissociation would be sufficient to start the chain process. Nevertheless, Miller and co-workers suggested the possibility of an initiation process [113–115] in which molecular fluorine reacts with a hydrocarbon molecule to yield an alkyl radical, hydrogen fluoride and a fluorine atom (Figure 2.21). RH

+

F2

R

+

HF

+

∆H = +16.3 kJmol−1

F

½113115


Figure 2.21

This is an attractive idea and there is ample precedent for this process with other halogens [116]. In reactions of fluorine with alkenes, the thermodynamics are more convincing [112] and there appears to be some supporting experimental evidence (Figure 2.22). C

C

+

F

F2

C

C

+

F

∆H

= −156.9 kJmol−1

½112


Figure 2.22

It was shown that a mixture of tetrachloroethene and chlorine did not react until a trace of fluorine was introduced, whereupon chlorination took place [114] (Figure 2.23). CCl2=CCl2

+

Cl2

F2 (trace)

CCl3-CCl3

85%

½114


Figure 2.23

Also, it has been suggested that dimerisation of haloalkenes observed during the interaction with fluorine at low temperatures (< 508 C) arises by a free-radical chain mechanism initiated in this way [115].

C Control of fluorination A consideration of the thermodynamics of fluorination reactions shows that the overall energy released upon substituting a hydrogen by fluorine [111] (430 kJmol1) is sufficient to cause carbon–carbon bond cleavage (ca. 355 kJmol1) leading to substrate degradation. Consequently, after many early attempts to effect direct fluorination had resulted in violent reactions, it was not until effective methods were developed for dissipating the considerable heat generated that any real progress was made [117, 118].

1 Dilution with inert gases It is possible to control direct fluorination reactions in their initial stages by using fluorine extensively diluted in an inert gas, such as nitrogen or helium, long reaction times, and by cooling the reactor to low temperatures. After partial fluorination of a substrate has been achieved, further fluorination generally requires more forcing conditions, since the substrate is now less activated towards radical substitution. Therefore, the concentration of fluorine and the temperature of the reaction may be raised to effect perfluorination. The ‘LaMar’ process has been developed by Lagow and Margrave with their co-workers [111,

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Preparation of Highly Fluorinated Compounds

37

117, 119, 120] to prepare many perfluoroalkanes [111, 121] and perfluoroadamantane derivatives as well as functional perfluoro compounds (Table 2.4 in Section E, below). In a related ‘aerosol fluorination’ technique [122–124], a substrate is absorbed onto fine particles of sodium fluoride which are then sprayed into a stream of dilute fluorine; many perfluorinated highly branched and cyclic alkanes have been prepared by this method. Other techniques for perfluorination with elemental fluorine make use of fluorocarbon solvents which act both as a heat sink in the early stages of fluorination and as a solvent to dissolve high concentrations of fluorine, which is helpful towards ensuring complete fluorination in the later ‘finishing’ stages [125, 126]. Perfluorination may be further aided by photolysis under UV irradiation [127] or by the addition of a highly reactive substrate, such as benzene [126], that also acts as a fluorine-atom generator (see above). Maintaining a high fluorine atom flux is at the heart of perfluorination techniques. Moderation of the early stages of direct fluorination may be achieved by further fluorination of partially fluorinated systems, where the first fluorine may be introduced by methodology that does not involve the use of elemental fluorine [128] (Figure 2.24). RFH CH3(-OCH2CH2-)nCH3 + CF2=CFCF3

½128


RFHCH2(-OCHCH2-)nCH2RFH

F2

RFH

= CF2CFHCF3

RF

= CF2CF2CF3

RF RFCF2(-OCFCF2-)nCF2RF

i, ii RFH

RFH

O

RFH

= CF2CFHCF3

RF

F O

91% RF RF

½129, 130


= CF2CF2CF3

i, 50% v:v F2 in N2; ii, Room temperature, then 280
C

Figure 2.24

Using these approaches, the successful further fluorination of partly fluorinated esters has been cleverly developed into a process for the synthesis of the important copolymer component perfluoro(propyl vinyl ether), PPVE [131] (Figure 2.25). A quite different, but realistic, approach to temperature control and efficient mixing involves the use of microreactors [129, 130, 132, 133]; a simple design is shown in Figure 2.26 [129]. These techniques are under active development but microreactor designs are now available that could be used on an industrial scale for the efficient and safe use of fluorine. Polyethylene vessels may be treated with fluorine in a blow moulding process (Airopakt, Air Products) so as to provide a fluorocarbon coating [134], but it seems highly unlikely that this treatment can be regarded as simply providing a polytetrafluoroethene (PTFE)

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38

Chapter 2 HOCH2CH(CH3)OC3F7

+

FC(O)CF(CF3)OC3F7

½131


C3F7OCF(CF3)C(O)OCH2CH(CH3)OC3H7 F2 C3F7OCF(CF3)C(O)OCF2CF(CF3)OC3F7 ∆ 2 FC(O)CF(CF3)OC3F7 i) NaOH ii)Heat CF2=CFOC3F7

PPVE

Figure 2.25

Figure 2.26

Reprinted with the permission of the Royal Society of Chemistry

surface [135, 136]. Such containers [137] possess excellent resistance to hydrocarbon solvent penetration [135, 138], probably because of enhanced cross-linking in the surface, and have been used successfully as fuel tanks by the automobile industry for many years. Other techniques of surface fluorination and oxyfluorination have been used to modify polymer surfaces.

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Preparation of Highly Fluorinated Compounds

D

39

Fluorinated carbon [139]

Fluorination of graphite at high temperature (300–5008 C) gives a white powder which approximates to the composition (CF)n . X-ray studies indicate that the fluorine atoms are strongly bonded to carbon but are contained between the graphite layers [140]. Graphite fluorides have similar properties to PTFE and have been exploited commercially as speciality lubricants and in high-performance lithium batteries [141]. Direct fluorination of Buckminsterfullerene, C60 , has been studied by several groups [142]. It is claimed that C60 F48 can be isolated as an intact sphere [143] and, moreover, as a single isomer after fluorination at 2508 C. Photoelectron spectroscopy studies suggest that as the level of fluorination is raised above C60 F48 , carbon–carbon bond cleavage occurs, thus cracking the sphere [144, 145]. A fluoroxyfullerene, C60 F17 OF, has been characterised [146]. Mesophase pitch, derived from coal tar, reacts smoothly with fluorine to give pitch fluoride [147, 148] with a composition between CF1:3 and CF1:6 , as a yellowish white solid which differs from graphite fluoride in that it is soluble in some fluorocarbon solvents. Consequently, thin films of pitch fluoride may be deposited on materials and the resulting surfaces have been claimed to have even lower surface energies than PTFE.

E

Fluorination of compounds containing functional groups

When functional groups are present, the products can be quite complex. Primary and secondary amines give NF2 and NF compounds respectively and fluorination of sulphur compounds gives products in which the sulphur has been oxidised to its maximum valency state of six [149] (Table 2.4). Hydroxy compounds can give fluoroalkyl hypofluorites (fluoroxy compounds) (see also Chapter 3, Section IIIB), the corresponding alkyl derivatives not being stable [150, 151]; bisfluoroxy derivatives have also been isolated [152–154] (Figure 2.27). i CH3OH

CF3OF

½150


i, F2, Cu/Ag, 160−180
C

CO2

i

CF2(OF)2

½153


i, F2, CsF, −196
C to rt

Figure 2.27

Perfluorinations of many ethers [155], cryptands [156], polyethers [119, 157], including the largest perfluoro-macrocycle [158], perfluoro [60]-crown-20 [123, 159], and the first perfluorinated sugar [160], orthocarbonates [161, 162], ketones [163, 164], esters [124, 165], phosphanes [166] and alkyl halides [167, 168] have been successfully accomplished by the LaMar or aerosol processes (Table 2.4).

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40

Chapter 2

Table 2.4 Fluorination using dilute fluorine Starting material

Product

Yield (%)

Ref.

89

[169]

96

[170]

26

[171]

–

[172]

91

[149]

Conditions: F2 in He or N2 , 788 C to rt (CH3 )3 CCH2 CH2 C(CH3 )3

(CF3 )3 CCF2 CF2 C(CF3 )3 F

C

C 4

4 F

F F3C H3C

F

F3C

H3C CH2CH2O

CF2CF2O

n

(CH3)3CCH2SH

n

(CF3)3CCF2SF5

Conditions: 268 C and lower CH2CH2O

CF2CF2O

20

[159] 20

Conditions: 908 C to rt O

O

F2

O

O O

F3C

O

O

F O

[160]

O

F3C

F CF3 O F3C

Conditions: Aerosol fluorination Cl

Cl

F

O

O O

F3C

CF2

60

[173]

65

[124]

CF3 F

O CF3

V HALOGEN FLUORIDES The reactions of halogen fluorides with organic compounds have been reviewed [174, 175] but their usefulness for the preparation of highly fluorinated substrates is limited to reactions with the corresponding perhalo-organic compounds [176] (Figure 2.28).

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Preparation of Highly Fluorinated Compounds BrF3

CBr4 CI4

IF5

CF3Br CF3I

41

½176


94%

95%

Figure 2.28

Liquid-phase halogenation of hexachlorobenzene with chlorine trifluoride appears to proceed by a series of additions and vinylic and allylic substitutions until all of the hexachlorobenzene is converted into chlorofluorocyclohexenes, C6 Fn (Cl10n ) (n ¼ mainly 4, 5 and 6), and conversion to cyclohexane derivatives occurs only upon the passage of quite a large excess of chlorine trifluoride [177] (Figure 2.29). The cyclohexene derivatives produced mainly retain the structure 2CCl5CCl2. A mixture of iodine with iodine pentafluoride, or bromine with bromine trifluoride, will add iodine monofluoride or bromine monofluoride respectively to fluorinated alkenes; this constitutes a very convenient route to the corresponding monohalopolyfluoroalkanes [178, 179], which is of considerable importance to the surfactant business (Figure 2.30). C6Cl6

ClF3, 240
C

C6F7Cl3 (2%) + C6F6Cl4 (10%) + C6F4Cl4 (4%)

½177


+ C6F5Cl5 (30%) + C6F4Cl6 (35%)

Figure 2.29

2I2

+

IF5

+

5CF2=CF2

2I2

+

IF5

+

5CF3CF=CF2

5CF3CF2I 150
C

5(CF3)2CFI

86%

½178, 179


99%

Figure 2.30

REFERENCES 1 2 3 4 5 6 7 8 9 10 11

G.C. Finger in Advances in Fluorine Chemistry, Vol. 2, ed. M. Stacey, J.C. Tatlow and A.G. Sharpe, Butterworth, London, 1961, p. 35. A.J. Rudge, The Manufacture and Use of Fluorine and its Compounds, Oxford University Press, London, 1962. M. Hudlicky, Chemistry of Organic Fluorine Compounds, 2nd revised edition, Ellis Horwood, Chichester, 1992. R. Miethen and D. Peters in Houben-Weyl: Methods of Organic Chemistry. Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 95. B. Baasner, H. Hegemann and J.C. Tatlow (eds), Houben-Weyl: Methods of Organic Chemistry. Vol. E10a, Organo-fluorine Compounds, Georg Thieme, Stuttgart, 1999. R. Stephens and J.C. Tatlow, Quart. Rev., 1962, 16, 44. A.K. Barbour, L.J. Belf and M.W. Buxton, Adv. Fluorine Chem., 1963, 3, 181. G.G. Furin and V.V. Bardin in New Fluorinating Agents in Organic Synthesis, ed. L. German and S. Zemskov, Springer-Verlag, Berlin, 1989, p. 117. M.A. McClinton and D.A. McClinton, Tetrahedron, 1992, 48, 6555. A. Marhold and E. Klauke, J. Fluorine Chem., 1981, 18, 281. G.A. Olah, G.K.S. Prakash, and J. Sommer, Superacids, Wiley, New York, 1985.

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12 J.M. Hamilton, Adv. Fluorine Chem., 1963, 3, 117. 13 B.E. Smart and R.E. Fernandez in Kirk-Othmer Encyclopedia of Chemical Technology, 4th edition, Vol. 11, ed. M. Howe-Grant, John Wiley and Sons, New York, 1994, p. 499. 14 A.J. Elliot in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 145. 15 V.N.M. Rao in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 159. 16 A.L. Henne, M.W. Renoll and H.M. Leicester, J. Am. Chem. Soc., 1939, 61, 938. 17 L.V. Johnson, F. Smith, M. Stacey and J.C. Tatlow, J. Chem. Soc., 1952, 4710. 18 A.L. Henne, A.M. Whaley and J.K. Stevenson, J. Am. Chem. Soc., 1941, 63, 3478. 19 C.B. Miller and C. Woolf, US Pat. 2 803 665 (1957); Chem. Abstr., 1958, 52, 2047d. 20 W.E. Truce, G.H. Birum and E.T. McBee, J. Am. Chem. Soc., 1952, 74, 3594. 21 A.L. Henne and P. Trott, J. Am. Chem. Soc., 1947, 69, 1820. 22 A. Latif, J. Ind. Chem. Soc., 1953, 30, 524. 23 A.J. Leffler, J. Org. Chem., 1959, 24, 1132. 24 V.V. Bardin, A.A. Avramenko, G.G. Furin, V.A. Krasilnikov, A.I. Karelin, P.P. Tushin and V.A. Petrov, J. Fluorine Chem., 1990, 49, 385. 25 J.H. Holloway, E.G. Hope, P.J. Townson and R.L. Powell, J. Fluorine Chem., 1996, 76, 105. 26 L.R. Subramanian and G. Siegemund in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 548. 27 B.E. Smart in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 57. 28 I.N. Rozhkov and I.L. Knunyants, Dokl. Akad. Nauk. SSSR (Eng. Transl.), 1971, 199, 622. 29 A.J. Parker in Use of Dipolar Aprotic Solvents in Organic Chemistry, ed. R.A. Raphael, E.C. Taylor and H. Wynberg, Wiley-Interscience, New York, 1965, p. 1. 30 J.C. Clark and D. MacQuarrie, J. Fluorine Chem., 1987, 35, 591. 31 R.D. Chambers, J.A. Jackson, W.K.R. Musgrave and R.A. Storey, J. Chem. Soc., 1968, 2221. 32 R.D. Chambers, J. Hutchinson and W.K.R. Musgrave, J. Chem. Soc., 1964, 3573. 33 R.E. Banks, R.N. Haszeldine, J.V. Latham and I.M. Young, J. Chem. Soc., 1965, 594. 34 J.H. Clark, Chem. Rev., 1980, 80, 429. 35 G.G. Yakobson and N.E. Akhmetova, Synthesis, 1983, 169. 36 J.A. Wilkinson, Chem. Rev., 1992, 92, 505. 37 G. Resnati, Tetrahedron, 1993, 49, 9385. 38 N. Ishikawa, T. Kitazume, T. Yamazaki, Y. Mochida and T. Tatsuio, Chem. Lett., 1981, 761. 39 R.E. Banks, K.N. Mothersdale, A.E. Tipping, E. Tsiliopoulos, H.J. Cozens, D.E.M. Wotton and J.C. Tatlow, J. Fluorine Chem., 1990, 46, 529. 40 Y. Kimura and H. Suzuki, Tetrahedron Lett., 1989, 30, 1271. 41 T.P. Smyth, A. Carey and B.K. Hodnett, Tetrahedron, 1995, 51, 6363. 42 J.H. Clark, A.J. Hyde and D.K. Smith, J. Chem. Soc., Chem. Commun., 1986, 791. 43 T. Ando, S.J. Brown, J.H. Clark, D.G. Cork, T. Hanafusa, J. Ichichara, J.M. Miller and M.S. Robertson, J. Chem. Soc., Perkin Trans. 2, 1986, 791. 44 V.V. Aksenov, V.M. Vlasov, V.I. Danilkin, P.P. Rodionov and G.N. Shnitko, J. Fluorine Chem., 1990, 46, 57. 45 H. Liu, P. Wang and P. Sun, J. Fluorine Chem., 1989, 43, 429. 46 C.L. Liotta and H.P. Harris, J. Am. Chem. Soc., 1974, 96, 2250. 47 V.V. Aksenov, V.M. Vlasov, I.M. Moryakina, P.P. Rodionov, V.P. Fadeeva, V.S. Chertok and G.G. Yakobson, J. Fluorine Chem., 1985, 28, 73. 48 J.H. Clark and D.J. MacQuarrie, Tetrahedron Lett., 1987, 28, 111. 49 Y. Yoshida, Y. Kimura and M. Tomoi, Chem. Lett., 1990, 769. 50 S. Dermiek and Y. Sason, J. Org. Chem., 1985, 50, 879. 51 K.O. Christe, W.W. Wilson, R.D. Wilson, R. Bau and J.A. Feng, J. Am. Chem. Soc., 1990, 112, 7619.

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52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80

81 82 83 84 85 86 87 88 89 90 91 92 93

43

D. Albanese, D. Landini and M. Penso, J. Org Chem., 1998, 63, 9589. N. Yoneda, Tetrahedron, 1991, 47, 5329. R.D. Chambers, S.R. Korn and G. Sandford, J. Fluorine Chem., 1994, 69, 103. M. Hudlicky, Org. Reactions, 1988, 35, 513. A.S. Pilcher, H.L. Ammon and P. DeShong, J. Am. Chem. Soc., 1995, 117, 5166. W.B. Farnham and R.L. Harlow, J. Am. Chem. Soc., 1981, 103, 4608. K.O. Christe and W.W. Wilson, J. Fluorine Chem., 1990, 47, 117. A.G. Sharpe, Quart. Rev., 1957, 11, 49. G. Rotenberg, M. Royz, O. Arrad and Y. Sasson, J. Chem. Soc., Perkin Trans. 1, 1999, 1491. F.W. Hoffmann, J. Am. Chem. Soc., 1948, 70, 2596. W. Verbeck and W. Sundermeyer, Angew. Chem., Int. Ed. Engl., 1966, 5, 314. E. Gryszkiewicz-Trochimowski, A. Sporzynski and J. Wnuk, Rec. Trav. Chim., 1947, 66, 413. J.T. Maynard, J. Org. Chem., 1963, 28, 112. R.D. Chambers and A.R. Edwards, J. Chem. Soc., Perkin Trans 1, 1997, 3623. M. Stacey and J.C. Tatlow, Adv. Fluorine Chem., 1960, 1, 166. J. Burdon in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 655. R.S. Jessup, F.G. Brickwedde and M.T. Wechsler, J. Res. Nat. Bur. Stand., 1950, 44, 457. P.L. Coe, R.G. Plevey and J.C. Tatlow, J. Chem. Soc. C, 1969, 1060. J. Bailey, R.G. Plevey and J.C. Tatlow, J. Fluorine Chem., 1988, 39, 23. J. Bailey, R.G. Plevey and J.C. Tatlow, J. Fluorine Chem., 1987, 37, 1. R.G. Plevey, M.P. Steward and J.C. Tatlow, J. Fluorine Chem., 1973, 3, 259. R.G. Plevey, R.W. Rendell and M.P. Steward, J. Fluorine Chem., 1973, 3, 267. R.D. Chambers, D.T. Clark, T.F. Holmes, W.K.R. Musgrave and I. Ritchie, J. Chem. Soc., Perkin Trans 1, 1974, 114. J. Burdon, J.C. Creasey, L.D. Proctor, R.G. Plevey and J.R.N. Yeoman, J. Chem. Soc., Perkin Trans 2, 1991, 445. J. Burdon and I.W. Parsons, Tetrahedron, 1975, 31, 2401. J. Burdon and I.W. Parsons, Tetrahedron, 1980, 36, 1423. R.D. Chambers, B. Grievson, F.G. Drakesmith and R.L. Powell, J. Fluorine Chem., 1985, 29, 323. R.W. Rendell and B. Wright, Tetrahedron, 1979, 35, 2405. R.D. Fowler, W.B. Burford, J.M. Hamilton, R.G. Sweet, C.E. Weber, J.S. Kasper and I. Litant in Preparation, Properties and Technology of Fluorine and Organic Fluoro-campounds, ed. C. Slesser and S.R. Schram, McGraw-Hill, New York, 1951, p. 349. B.D. Joyner, J. Fluorine Chem., 1986, 33, 337. R.N. Haszeldine and F. Smith, J. Chem. Soc., 1950, 3617. A.K. Barbour, G.B. Barlow and J.C. Tatlow, J. Appl. Chem., 1952, 2, 127. R.G. Plevey, R.W. Rendell and J.C. Tatlow, J. Fluorine Chem., 1982, 21, 413. P. Johncock, R.H. Mobbs and W.K.R. Musgrave, Ind. Eng. Chem., Proc. Res. Dev., 1962, 1, 267. R.W. Rendell and B. Wright, Tetrahedron, 1978, 34, 197. F.G. Drakesmith in Organofluorine Chemistry. Techniques and Synthons, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 197. J.H. Simons in Fluorine Chemistry, Vol. 1, ed. J.H. Simons, Academic Press, New York, 1950, p. 401. J. Burdon and J.C. Tatlow, Adv. Fluorine Chem., 1960, 1, 129. S. Nagase, Fluorine Chem. Rev., 1967, 1, 77. N. Watanabe, J. Fluorine Chem., 1983, 22, 205. P. Sartori, Bull. Electrochem., 1990, 6, 471. T. Abe and S. Nagase in Organofluorine Chemistry. Preparation, Properties and Industrial Applications, ed. R.E. Banks, Ellis Horwood, Chichester, 1982, p. 19.

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Chapter 2

94 Y.W. Alsmeyer, W.V. Childs, R.M. Flynn, G.G.I. Moore and J.C. Smeltzer in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 121. 95 K. Pohmer and A. Bulan in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 305. 96 A. Dimitrov, S. Rudiger, N.V. Ignatyev and S. Datchenkov, J. Fluorine Chem., 1990, 50, 197. 97 J. Burdon and I.W. Parsons, Tetrahedron, 1972, 28, 43. 98 E.A. Kauck and J.H. Simons, G.B. Pat. 666 733 (1952); Chem. Abtsr., 1952, 46, 6015c. 99 R.E. Banks, W.M. Cheng and R.N. Haszeldine, J. Chem. Soc., 1962, 3407. 100 A.F. Clifford, H.K. El-Shamy, H.J. Emele´us and R.N. Haszeldine, J. Chem. Soc., 1953, 2372. 101 H.M. Scholberg and H.G. Bryce, US Pat. 2 717 871 (1955); Chem. Abstr., 1955, 49, 15572 h. 102 H.W. Prokop, H.J. Zhou, S.Q. Xu, C.H. Wu, S.R. Chuey and C.C. Liu, J. Fluorine Chem., 1989, 43, 257. 103 T. Gramstad and R.N. Haszeldine, J. Chem. Soc., 1956, 173. 104 R.D. Chambers, R.W. Fuss, M. Jones, P. Sartori, A.P. Swales and R. Herkelmann, J. Fluorine Chem., 1990, 49, 409. 105 N. Bartlett, R.D. Chambers, A.J. Roche, R.C.H. Spink, L. Chacon and J.M. Whalen, J. Chem. Soc., Chem. Commun., 1996, 1049. 106 J.M. Whalen, L. Chacon and N. Bartlett, Proc. Electrochem. Soc., 1997, 97-15, 1. 107 J.M. Whalen, L.C. Chacon and N. Bartlett in The Oxidation of Oxygen and Related Chemistry – Selected Papers of Neil Bartlett, ed. N. Bartlett, World Scientific, Singapore, 2001, p. 395. 108 K.O. Christe, Inorg. Chem., 1986, 25, 3721. 109 K.O. Christe, N. Watanabe, T. Tojo, S. Rozen, R.J. Lagow, J. Adcock, D.T. Meshri and D.B. Hage in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 159. 110 J.F. Ellis and G.F. May, J. Fluorine Chem., 1986, 33, 133. 111 R.J. Lagow and J.L. Margrave, Prog. Inorg. Chem., 1979, 26, 161. 112 J.M. Tedder, Adv. Fluorine Chem., 1961, 2, 104. 113 W.T. Miller and A.L. Dittman, J. Am. Chem. Soc., 1956, 78, 2793. 114 W.T. Miller, S.D. Koch and F.W. McLafferty, J. Am. Chem. Soc., 1956, 78, 4992. 115 W.T. Miller and S.D. Koch, J. Am. Chem. Soc., 1957, 79, 3084. 116 W.A. Pryor, Free Radicals, McGraw-Hill, New York, 1966. 117 R.R. Lagow in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 188. 118 S. Rozen in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 167. 119 R.J. Lagow, T.R. Bierschenk, T.J. Juhlke and H. Kawa in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and G.K.S. Prakash, John Wiley and Sons, New York, 1992, p. 97. 120 R.J. Lagow in Kirk-Othmer Encyclopedia of Chemical Technology, 4th edition, Vol. 11, ed. M. Howe-Grant, John Wiley and Sons, New York, 1994, p. 482. 121 W.H. Lin and R.J. Lagow, J. Fluorine Chem., 1990, 50, 345. 122 J.L. Adcock, K. Horita and E.B. Renk, J. Am. Chem. Soc., 1981, 103, 6937. 123 J. Adcock in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 202. 124 J.L. Adcock in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and G.K.S. Prakash, John Wiley and Sons, New York, 1992, p. 127. 125 T.R. Bierschenk, T. Juhlke and R.J. Lagow, WO Pat. 87/02 992 (1987); Chem. Abstr., 1987, 107, 176772v. 126 T.R. Bierschenk, T. Juhlke, H. Kawa and R.J. Lagow, WO Pat. 90/03 353 A1 (1990); Chem. Abstr., 1991, 114, 231007 w. 127 T. Ono, K. Yamanouchi and K.V. Scherer, J. Fluorine Chem., 1995, 73, 267. 128 R.D. Chambers, A.K. Joel and A.J. Rees, J. Fluorine Chem., 2000, 101, 97.

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Preparation of Highly Fluorinated Compounds

129 130 131 132 133 134

135 136 137 138 139 140 141 142 143 144 145

146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166

45

R.D. Chambers and R.C.H. Spink, J. Chem Soc., Chem. Commun., 1999, 883. R.D. Chambers, D. Holling, R.C.H. Spink and G. Sandford, Lab on a Chip, 2001, 1, 132. T. Okazoe, K. Watanabe, M. Itoh, D. Shirakawa, H. Morofushi, H. Okamoto and S. Tatematsu, Adv. Sci. Synth., 2001, 343, 215. K. Jahnisch, M. Baerns, V. Hessel, W. Erhfeld, V. Haverkamp, H. Lowe, C. Wille and A. Gruber, J. Fluorine Chem., 2000, 105, 117. N. deMas, A. Gunther, M.A. Schmit and K.F. Jensen, Ind. Eng. Chem. Res., 2003, 42, 698. M. Anand, J.P. Hobbs and I.J. Brass in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 469. F.J. du Toit and R.D. Sanderson, J. Fluorine Chem., 1999, 98, 107. A.P. Kharitonov, Pop. Plastics Packaging, 1997, 75. Various authors, Ind. Res. Dev., 1978, 12, 102. J.P. Hobbs, P.B. Henderson and M.R. Pascolini, J. Fluorine Chem., 2000, 104, 87. D.T. Meshri and D.B. Hage in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 209. N. Watanabe, T. Nakajima and H. Touhara, Graphite Fluorides, Elsevier, New York, 1988. G.A. Shia and G. Mani in Organofluorine Chemistry. Principles and Commercial Applications., ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 483. K. Kniaz, J.E. Fischer, H. Selig, G.B.M. Vaughan, W.J. Romanow, D.M. Cox, S.K. Chowdhury, J.P. McCauley, R.M. Strongin and A.B. Smith, J. Am. Chem. Soc., 1993, 115, 6060. A.A. Gakh, A.A. Tuinman, J.L. Adcock, R.A. Sachleben and R.N. Compton, J. Am. Chem. Soc., 1994, 116, 819. A.A. Tuinman, A.A. Gakh, J.L. Adcock and R.N. Compton, J. Am. Chem. Soc., 1993, 115, 5885. D.M. Cox, S.D. Cameron, A. Tuinman, A. Gakh, J.L. Adcock, R.N. Compton, E.W. Hagaman, K. Kniaz, J.E. Fischer, R.M. Strongin, M.A. Cichy and A.B. Smith, J. Am. Chem. Soc., 1994, 116, 1115. A.D. Darwish, A.K. Abdul-Sada, A.G. Avent, S.M. Street and R. Taylor, J. Fluorine Chem., 2003, 121, 185. H. Fujimoto, M. Yoshikawa, A. Mabuchi and T. Maeda, J. Fluorine Chem., 1992, 57, 65. H. Fujimoto, A. Mabuchi, T. Maeda, Y. Matsumara, N. Watanabe and H. Touhara, Carbon, 1992, 30, 851. H.N. Huang, H. Roesky and R.J. Lagow, Inorg. Chem., 1991, 30, 789. K.B. Kellog and G.H. Cady, J. Am. Chem. Soc., 1948, 70, 3986. J.H. Prager, J. Org. Chem., 1966, 31, 392. P.G. Thompson, J. Am. Chem. Soc., 1967, 89, 1811. R.L. Cauble and G. Cady, J. Am. Chem. Soc., 1967, 89, 1962. F.A. Hohorst and J.M. Shreeve, J. Am. Chem. Soc., 1967, 89, 1809. D.F. Persico, H.N. Huang, R.J. Lagow and L.C. Clark, J. Org. Chem., 1985, 50, 5156. W.D. Clark, T-Y. Lin, S.D. Maleknia and R.J. Lagow, J. Org. Chem., 1990, 55, 5933. K.S. Sung and R.J. Lagow, J. Am. Chem. Soc., 1995, 117, 4276. M. Biollaz and J. Kalvoda, Helv. Chim. Acta, 1977, 60, 2703. H-C. Wei and R.J. Lagow, J. Chem. Soc., Chem. Commun., 2000, 2139. T.-Y. Lin, H-C. Chang and R.J. Lagow, J. Org. Chem., 1999, 64, 8127. W-H. Lin, W.D. Clark and R.J. Lagow, J. Org. Chem., 1989, 54, 1990. J.L. Adcock, M.L. Robin and S. Zuberi, J. Fluorine Chem., 1987, 37, 327. J.L. Adcock and M.L. Robin, J. Org. Chem., 1983, 48, 2437. J.L. Adcock and H. Luo, J. Org. Chem., 1992, 57, 4297. J.L. Adcock and R.J. Lagow, J. Am. Chem. Soc., 1974, 96, 7588. J.J. Kampa, J.W. Nail and R.J. Lagow, Angew. Chem., Int. Ed. Engl., 1995, 34, 1241.

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46

Chapter 2

167 168 169 170 171 172 173 174 175

J.L. Adcock, W.D. Evans and L. Heller-Grossman, J. Org. Chem., 1983, 48, 4953. J.L. Adcock and W.D. Evans, J. Org. Chem., 1984, 49, 2719. E.K.S. Liu and R.J. Lagow, J. Fluorine Chem., 1979, 14, 71. R.E. Aikman and R.J. Lagow, J. Org. Chem., 1982, 47, 2789. G. Robertson, E.K.S. Liu and R.J. Lagow, J. Org. Chem., 1978, 43, 4981. G.E. Gerhardt and R.J. Lagow, J. Org. Chem., 1978, 43, 4505. J.L. Adcock, H. Luo and S.S. Zuberi, J. Org. Chem., 1992, 57, 4749. W.K.R. Musgrave, Adv. Fluorine Chem., 1960, 1, 1. L.S. Boguslavskaya and N.N. Chuvatkin in New Fluorinating Agents in Organic Synthesis, ed. L. German and S. Zemskov, Springer-Verlag, Berlin, 1989, p. 140. A.A. Banks, H.J. Emele´us, R.N. Haszeldine and V. Kerrigan, J. Chem. Soc., 1948, 2188. R.D. Chambers, J. Heyes and W.K.R. Musgrave, Tetrahedron, 1963, 19, 891. R.D. Chambers, W.K.R. Musgrave and J. Savory, J. Chem. Soc., 1961, 3779. M. Hauptschein and M. Braid, J. Am. Chem. Soc., 1961, 83, 2383.

176 177 178 179

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Chapter 3

Partial or Selective Fluorination

I

INTRODUCTION

Whereas the previous chapter dealt largely with the synthesis of highly fluorinated systems, here we will be concerned with methods available for introducing mainly one, or two, fluorine atoms at specific points in a molecule, although many of these processes can, of course, be applied to already partly fluorinated systems in order to introduce more fluorine. The merits and importance of introducing a single fluorine atom into biologically significant compounds was discussed in Chapter 1, and many reviews are available concerning the synthesis of selectively fluorinated compounds [1–20]; the reader is directed to these for comprehensive literature coverage. The following discussion is intended to illustrate the types of reagents required to effect replacement of a wide range of functional groups.

II

DISPLACEMENT OF HALOGEN BY FLUORIDE ION

A

Silver fluoride

Much early work [21] involved the use of silver(I) fluoride, conveniently prepared from the oxide or carbonate with 40% hydrogen fluoride, for the exchange of single halogen atoms in alkyl halides [22] and other systems [23]. The use of calcium fluoride as a solid, inert support may increase the reactivity of silver fluoride [24] (Figure 3.1). Br

F i

CH3(CH2)15

CO2Me

CH3(CH2)15

CO2Me

84%

½24


i AgF, CH3CN, H2O, 80
C, 2hr i C8H17I

C8H17F

80%

i AgF, CaF2, 75
C, 10min

Figure 3.1

B

Alkali metal fluorides (see also Chapter 2, Section IIB)

Potassium fluoride is used most frequently as a balance between reactivity and economy, because efficiency decreases in the series CsF > KF > NaF. Different forms of KF are available and a number of ‘catalysts’ have been used to enhance the reactivity of KF in Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

47

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48

Chapter 3

aprotic solvents (see Chapter 2, Section IIB). Acid fluorides, alkyl fluorides and fluoroaromatics are obtained from the corresponding chlorides by reaction with potassium fluoride (Figure 3.2). Surprisingly, although it is usually stressed (as we have done in Chapter 2) that a metal fluoride should be dry, because fluoride ion is deactivated by its co-ordination sphere in aqueous solution, the addition of small amounts of water is necessary to obtain halogen exchange [25]. Alternatively, phase-transfer agents or crown polyethers may achieve the same result. It is the author’s view that these additions are necessary to remove other metal halide impurities from the surface of the fluoride,

i

CH3COCl i,

½29


76%

CH3COF

KF, CH3COOH, 100
C i

C6H5CHCHSO2Cl

C6H5CHCHSO2F

½30


51%

i, KF, xylene, reflux i or ii

MF + n-C8H17Br

i, MF = KF plus small amounts water, 85
C ii, MF = Bu4NF.3H2O, 60
C 71% i

MF + BrCH2COOEt i, MF

= CsF

½25


n-C8H17F + MBr 60%

70%

½25


O(CH2)3F

½27


FCH2COOEt + MBr

+ 10% Bu4NF, 40
C

O(CH2)3OMs i

Me i, KF,

92%

Bu N

N

BF4 , H2O (5 equiv), 100
C

i FCH2CH2OH

BrCH2CH2OH

72%

½28


i CH3CH2CHBrCOOEt

CH3CH2CHFCOOEt

78%

i, KF, Hexadecyltributylphosphonium bromide, heat

Figure 3.2

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 49

Partial or Selective Fluorination

49

because electron spectroscopy for chemical analysis (ESCA) results have demonstrated [26] that the other metal halide impurities are concentrated on the surface of the fluoride, even in samples that are ‘pure’ by bulk analysis. More remarkable is the fact that, using an ionic liquid as solvent, addition of five equivalents of water gave high reactivity and no elimination product [27]. A semi-molten mixture of potassium fluoride in hexadecyltributylphosphonium bromide (m.p. 56–588 C) is surprisingly effective [28] (Figure 3.2).

C

Other sources of fluoride ion

The low solubility, highly hygroscopic nature and low reactivity of alkali metal fluorides, and the sometimes harsh reaction conditions required for these fluorides to effect halogen exchange, have prompted a search for a source of fluoride ion that is easily handled, highly reactive, selective and soluble in organic solvents; several reagents possessing organic, lipophilic counter-ions have been developed for this task with varying degrees of success [18]. Maximum fluoride ion nucleophilicity is achieved if the reagents are free from moisture; tetrabutylammonium fluoride (TBAF), obtained commercially as the trihydrate, can be partially dried either by heating at 408 C under high vacuum [31] or, chemically, by reaction with hexamethyldisilazane [32], but prolonged heating of TBAF causes decomposition to occur via a Hofmann elimination pathway [33]. However, tetramethylammonium fluoride [34] and adamantyltrimethylammonium fluoride [35] are more stable and they can be obtained in an anhydrous state by heating under vacuum after recrystallisation from propanol. Fluoride ion sources have been described that contain more elaborate counter-ions including tris(dimethylamino)sulphonium difluorotrimethylsiliconate (TAS-F) [12], a phosphazenium fluoride [36], cobaltocenium fluoride [37] and ‘Proton Sponge’ (PS) [38] (Table 3.1). Table 3.1 Halogen exchange by various sources of fluoride ion Substrate

Reagent/Conditions

Product

CH2 ¼ CHCH2 Br

Bu4 NF, 258 C

CH2 ¼ CHCH2 F

O Cl

Ref.

85

[33]

O

THF=HMPTa , 958 C, Bu4 Nþ HF 2

Ph

Yield (%)

[39] F

Ph

RX (R ¼ alkyl, X ¼ Cl, Br)

2Bu4 NFnH2 O CH3 CN

RF

PhCH2 Br

Ph4 PHF2 CH3 CN, 508 C

PhCH2 F

100

[41]

PhCH2 Cl

Cp2 CoFb THF, rt

PhCH2 F

95

[37]

C2 H5 I

TAS-Fc CH3 CN, rt

C2 H5 F

85

[12]

[40]

Contd

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 50

50

Chapter 3

Table 3.1 Contd Substrate

Reagent/Conditions

Product

CH3 ðCH2 Þ7 Br

Bu4 Nþ Ph3 SiF 2 CH3 CN, 808 C

CH3 ðCH2 Þ7 F

O

O Ph a

85

[42]

76

[38]

F

Ph O

Pyridine9HF 08 C

Cl

Ref.

O

PS=HFd CH3 CN, rt

Cl

Ph

Yield (%)

[43] Ph

F

HMPT, hexamethylphosphoric triamide. b

c

Cp2CoF

d

TAS-F

+ − [(Me2N)3S] [(CH3)3SiF2]

Co

Me2N

PS / HF NMe2

F

. HF

Hydrogen fluoride under vigorous conditions may be used in favourable circumstances, for example to make fluoromethyl ethers [44] (Figure 3.3a). OH

+

Cl

OCCl3

OCF3

Cl

Cl

½44


i CCl4

i, HF, 150
C

70%

Figure 3.3a

Aromatic systems need to be activated towards nucleophilic attack to enable halogen exchange to occur (see Chapter 9) and the sulphonyl group has been employed as a disposable activating group [45] (Figure 3.3b). Addition of triphenyltin fluoride is claimed to be beneficial [46].

D Miscellaneous reagents Alkyl bromides are effectively transformed into alkyl fluorides by both chlorine monofluoride [47] (Figure 3.4) and the less reactive bromine trifluoride [48–50]. Since tertiary

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 51

Partial or Selective Fluorination

R

R

Cl

F

½45


i Cl

SO2Cl R i, ii, iii,

51

Cl

SO2F ii, iii

= H, Me KF, Ph4PBr NaOH H2SO4, heat

R

F

Cl

Figure 3.3b

CH3CH2CH2Br

+

ClF

0
C

CH3CH2CH2F

70%

30% rt CH2ClCH2Br

+

CH2ClCH2F

BrF3

½47


+ CH3CHFCH3

½48, 49


80%

Figure 3.4

bromides react the most readily, and rearrangement occurs on reaction with primary alkyl bromides, a carbocationic mechanism has been proposed. The use of p-iodotoluene difluoride for replacement of iodine by fluorine has beeen described as a nucleophilic displacement of IF2 , as a good leaving group, in a pre-formed iodoalkane difluoride [51]. Note that iodine is displaced in preference to p-TsO in this system (Figure 3.5a). i

RCH2I R

= p-TsO

RCH2

IF2

F

RCH2F

½51


74%

i, p-MeC6H4IF2, Et3N.4HF, CH2Cl2

Figure 3.5a

However, a Pummerer-type process is involved in the introduction of two fluorine atoms into phenylsulphanated lactams [52] (Figure 3.5b, p. 52). The reaction of fluorine or xenon difluoride with iodoalkanes gives fluoroalkanes by similar processes [53, 54].

III

REPLACEMENT OF HYDROGEN BY FLUORINE [55, 56]

A

Elemental fluorine

From the previous discussion on extensive fluorination (Chapter 2, Section IV) it might be assumed that, in general, it will be very difficult to effect the selective replacement of hydrogen by fluorine in preparatively useful reactions. This has been the perceived wisdom in the past but the situation is changing rapidly [56].

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 52

52

Chapter 3

Ar O

I

O

PhS

PhS

PhS N

F O

ArIF2

N

N

ArIF2

½52


F

O

O PhS

PhS N

F

N F

F

F

Figure 3.5b

The first indication that fluorine could be used as a selective fluorinating agent was reported by Bockemu¨ller in 1933 concerning reactions with butyric acid [57]. Fluorination only occurs at the b- and g- positions, demonstrating that the regioselectivity of the process can be heavily influenced by the presence of an electron-withdrawing group in the substrate. This demonstrates the electrophilic nature of fluorine, although lowtemperature fluorination of hydrocarbons is still much less selective than the corresponding chlorinations [58]. However, hydrogen atoms attached to tetrahedral carbon, through orbitals with a high p contribution, can be selectively replaced by fluorine when the reaction is carried out using a polar solvent such as chloroform or nitromethane [11, 59–61]. Even tertiary hydrogens in steroids may be selectively replaced using fluorine [62, 63] (Figure 3.6). It has been demonstrated that acetonitrile can be an effective solvent for these reactions, crucially allowing reactions to be carried out at higher temperatures [64, 65] (Figure 3.7).

1 Elemental fluorine as an electrophile The question arises as to whether these reactions involve molecular fluorine as an electrophile or electrophilic fluorine atoms. In principle, nucleophilic attack on fluorine could be promoted in a number of ways. Interaction of the leaving group, which in this case is fluoride, with a protonic or Lewis acid has been demonstrated [66] (Figure 3.8) and we will see that reagents containing bonds from fluorine to oxygen or, especially, to nitrogen (which provide excellent leaving groups) are particularly effective. For some reactions with saturated hydrocarbons, an electrophilic process involving a non-classical three-centre, two-electron transition state similar to other electrophilic substitutions at s-bonds [67] has been suggested [11, 65] (Figure 3.9). The facts that the stereochemistry is retained [11, 65] and products of elimination or rearrangement are not observed, as well as the result of ab initio calculations relating to the fluorination of methane [68], provide support for this argument. Moreover, there is a very close parallel between the products arising from reactions of elemental fluorine and of Selectfluort (see Section IIIC) with alkanes and cycloalkanes [64, 65]. There is an even stronger case for

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 53

Partial or Selective Fluorination

53

F i

½62, 63


+

OR

OR

OR

F

F

60%

10%

R = −CO-C6H4NO2 i, F2, N2, −70
C, CHCl3, CFCl3 (1:1) OAc

OAc

i F

H AcO

AcO 50%

i, F2 in N2(10% v/v), C6H5-NO2, −78
C, CFCl3, CHCl3

Figure 3.6

H

F i

½11, 64, 65


54%, 68% conversion

H

H

i, F2 in N2 (10% v/v), CH3CN, 0
C

Figure 3.7

Nu:

+

F

F

Nuc

H

COOH

COOH

F i

F

F i, F2/N2, 98% H2SO4, room temp.

Figure 3.8

H

+

HF

½66


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54

Chapter 3 H H

F F

F

½11, 65


HCCl3

OCOC6H4NO2

OCOC6H4NO2 i 60% Me

Me

F

i, F2, N2, −70
C, CHCl3, CFCl3 (1:1)

Figure 3.9

N–F reagents acting as electrophiles, because radical clock experiments with these systems do not support a radical process [69, 70]. Consequently, in a given situation, the question as to whether a fluorination involves fluorine atoms (which themselves are very electrophilic, and such processes will therefore have polar characteristics) or nucleophilic attack on a molecule of elemental fluorine is difficult to assess. Both processes almost certainly occur, depending on the system and conditions. The changing perspective on the viability of fluorine as a reagent is illustrated by the fact that many selective fluorinations of substrates [8] containing carbon centres of high electron density have now been described, including a variety of enolate derivatives [71, 72], stabilised carbanions [73, 74], steroids [75] and 1,3-dicarbonyl derivatives [76] (Table 3.2) as well as some aromatic compounds [77]. Fluorinated aminoacids have been obtained by direct fluorination [78] (Figure 3.10). Table 3.2 Selective fluorinations with elemental fluorine Substrate

Conditions

OSiMe3

Product

OEt

Ref.

78

[71]

57

[79]

84

[74]

O

F2 , N2 788 C, CFCl3

OSiMe3

Yield (%)

F

O

F2 , N2 788 C, CFCl3

OEt F

NO2 OH O2N

H

i) OH ii) F2 , N2 , 58 C, H2 O

NO2 OH O2N

F

Contd

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Partial or Selective Fluorination

55

Table 3.2 Contd Substrate O

Conditions

Product

O

O OEt

F2 , N2 108 C, HCOOH

Yield (%)

Ref.

90

[76]

71

[80]

O OEt F

O

OH

O

OHC O

O

F2 , N2 408 C, CH3 CN

F O

O

O

R

COOMe

H

F2

O

COOMe F NHCOPh

RCHF

NHCOPh

COOH F NHCOPh

RCHF

½78


COOH F NH2

R = Alkyl or aryl RCHF

Figure 3.10

It has been established that elemental fluorine can be used to functionalise saturated sites in a two-step process using BF3 and this is one of the more direct methodologies, for this purpose, that has been described so far [65] (Figure 3.11). H

F

½65
i

H

Stereochemistry Retained

i, F2, CH3CN, 0
C ii, BF3.Et2O iii, CH3CN, H2O

ii

H

H iii O H N

H

Figure 3.11

Me

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Chapter 3

B Electrophilic fluorinating agents containing O–F bonds [81, 82] Several organic hypofluorites, including trifluoromethyl (CF3 OF) [83–85], perfluoroethyl (C2 F5 OF) [86], trifluoroacetyl (CF3 COOF) [87] and acetyl hypofluorite (CH3 COOF) [88, 89], are now known which have found applications as fluorinating agents [90–94] (Figure 3.12).

Nu:

+

F

Nu

OCF3

R' COOR''

R

R'

i, ii

OCF3

R'

OSiMe3

iii

COOR''

R

OR''

R

H

+

F

½89


F

i, LDA ii, Me3SiCl iii, MeCOOF

R = R' = n-Pr, R'' = Me, 90% R = Ph, R' = Et, R'' = Me, 80%

Figure 3.12

The ability of fluorine to act as an electrophile in these systems is achieved not so much by the withdrawal of electronic charge from fluorine but by the creation of excellent leaving groups attached to fluorine. If a good leaving group is not incorporated in this way, the hypofluorites can act as sources of positively charged alkoxonium ions, as in the cases of methyl and tert-butyl hypofluorite [95, 96] (Figure 3.13), rather than as electrophilic fluorinating reagents. F

OMe

R1

R2

60-70%

i R1

R2

i, MeOF, CH3CN, −40
C

C6H5-CH=CH2

i

Room Temp

δ+ C6H5-C F

i,

δ−

δ− CH δ+ Ot-Bu

t-BuOF, CH3CN

C6H5-CHFCH2Ot-Bu

Figure 3.13

½95


½96


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57

However, single-electron transfers promoted by photolysis, are the most likely processes when CF3 OF is used as the fluorinating reagent [93]. Examples of the use of hypofluorites for conversion of C2H to C2F bonds are given in Table 3.3. Table 3.3 Fluorinations using O–F reagents Substrate

Reagent/Conditions

NO2

Product F

i) MeONa, MeOH

Yield (%)

Ref.

85

[97]

86

[98]

72

[99]

NO2

ii) AcOF, CFCl3 , 08 C

O

O

F

i) LDA, THF ii) AcOF, 788 C O

O OEt

O

AcOF, CFCl3 , CHCl3 ,  758 C

O OEt F

Caesium fluoroxysulphate (CsSO4 F) [94] is a solid electrophilic fluorinating agent that is very easily prepared [100] (Figure 3.14) but, unfortunately, is very prone to rapid uncontrolled decomposition. However, it has been used for the fluorination of hydrocarbons [101] and aromatics [102–104] (Figure 3.15).

Cs2SO4

+

F2

H2O

CsSO3OF

½100


Figure 3.14

C6H5R

i

½102104


FC6H4R

i, CsSO3OF, BF3, CH3CN

p-XC6H4SnMe3

i

p-XC6H4F

i, CsSO3OF, CH3CN, −4 to 0
C X = H, 69%; = Cl, 87%; = Me 86%

Figure 3.15

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Chapter 3

C Electrophilic fluorinating agents containing N–F bonds [105–107] There is now available a range of stable, easily handled, solid electrophilic fluorinating agents of the N–F type. These remarkable reagents are generally prepared by reaction of a neutral base [108] or a salt [109] with fluorine (Figure 3.16). (CF3SO2)2NH

+

+

(CF3SO2)2NF

F2

HF

½108


CH2Cl

CH2Cl

N

N i

2BF4

BF4

½109


N

N i, F2, N2, NaBF4, CH3CN, −35
C

F

Selectfluor®

Figure 3.16

Reported reagents of this class include N-fluorobis(trifluoromethanesulphonyl)imide [110, 111], N-fluoro-N-alkyl-sulphonamides [112], dihydro-N-fluoro-2-pyridone [113], N-fluoropyridinium salts [114–116], N-fluoroquinuclidinium [117] and related salts [118, 119], N-fluoroperfluoroalkyl sulphonamides [120, 121] and N-fluorosultams [122], some of which are commercially available (e.g. Selectfluort, Air Products). Many fluorinations of resonance-stabilised carbanions [119], phosphonates [123], 1,3-dicarbonyls [124, 125], enol acetates [115], enol silyl ethers [119], enamines [119], aromatics (Chapter 9), double bonds and compounds containing carbon–sulphur bonds [126] have been performed under mild conditions (Table 3.4) and even enantioselective fluorinations of enolates are possible when appropriate homochiral N-fluorosultams are used [127, 128], or other homochiral substrates [129]. Considerable encouragement is given by reports of relatively high enantioselectivity in some processes where N–F compounds have been used in the presence of various chiral catalysts [130, 131], although the latter are currently used in significant proportions. Table 3.4 Fluorinations using electrophilic N–F fluorinating reagents Substrate

Reagent/Conditions Me

O

Product

Me

Ref.

O

Ph

Ph OMe

N

CH3

F

OMe CH3

S O

[122]

F

O

LDA, THF, 788 C to rt O

O n-Pr

P

OEt OEt

PhSO2 Þ2 NF LDA, THF

n-Pr

P F

OEt OEt

[123]

F

Contd

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Partial or Selective Fluorination

59

Table 3.4 Contd Substrate

Reagent/Conditions O

O

Product O

CF3 SO2 Þ2 NF CH2 Cl2 , rt

Ref.

O

[124]

F O

CH2Cl

O

Ph

NMe2

O

N

O

Ph

NMe2

−

2BF4

[125]

F

N F

CH3 CN, rt OSiMe3

O −

F

OTf

[115]

N F

CH2 Cl2 , reflux AcO

O

U

CH2Cl

AcO

O

U

N F −

[126]

2BF4 AcO

S-Ar

AcO

N

S-Ar

F

Et3 N, CH3 CN, rt O

O F

CO2Et

CO2Et

[127]

N S

F O

O

NaH, Et2 O, rt

It is frequently overlooked that, following fluorination, some of these systems, e.g. Selectfluort, are extremely acidic and may, consequently, ionise the carbon–fluorine bond just formed, leading to a carbocation and subsequent reaction with the solvent (see Section IIIA) [65]. These fluorinations are generally considered to proceed by nucleophilic attack on fluorine, rather than via an electron-transfer mechanism [115], as determined from radical

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60

Chapter 3

clock experiments [69, 70]. Consistent with this view, ionic liquids have been used as solvents for fluorinations of aromatic systems with Selectfluort [132, 133] and supercritical carbon dioxide has been used with 2,2’-bipyridinium fluorides [134].

D Xenon difluoride [135–137] This reagent acts as a source of electrophilic fluorine but the nature of the products can depend on the acidity of the glass surface of the vessel used. Otherwise a single electron transfer process may intervene [138] (Figure 3.17). X

X i

X = O, CH2

½139


F

i, XeF2, BF3.OEt2

OSiMe3

i) Aprotic conditions ii) Protic conditions

XeF2

XeF2 i O

ii O

O F

½138


O

F +

O +

Figure 3.17

Xenon difluoride has also been used for the fluorination of enol derivatives [5] and 1,3-dicarbonyl compounds [140], and fluorination of activated aromatic substrates is possible in the presence of a Lewis acid [141].

E

Miscellaneous

Fluorinations using perchloryl fluoride (FClO3) have been reported [17, 142] but, since the perchloric acid that is formed as a side-product gives an explosive mixture with organic compounds, this approach to selective fluorinations is not recommended. Fluorination of hydrocarbons, such as adamantane, is possible using a mixture of nitrosonium tetrafluoroborate and pyridineHF [143] (Figure 3.18). Oxidative fluorination of phenols in amineHF solution gives difluorodienones [144] (Figure 3.19). Fluorination of aromatic substrates has been reported [145].

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Partial or Selective Fluorination

R3CH

R3C

H

i

R3CF

R3C NO

−

61

½143


R3CNO

i, NO+BF4, Py.HF

Figure 3.18 OH

O i

½144


30% F

F

i, PbO2, Py.HF

Figure 3.19

Oxidative fluorination of toluene derivatives to the corresponding fluoromethylbenzenes is possible using appropriate lead or nickel complexes in liquid hydrogen fluoride, but fluorination becomes more difficult as the reaction progresses because fluorine substituents increase the oxidation potential of the substrate [146] (Figure 3.20). Consequently, it seems unlikely that the ECF process (Chapter 2, Section III) could proceed to perfluorination by an analogous mechanism. ArCH3

Pb(OAc)4

−H+

(ArCH3)

HF, −e

ArCH2

½146


−e

etc

ArCF2H

ArCH2F Ar

ArCH2

= p-C6H4NO2

Figure 3.20

a-Fluoro sulphides may be prepared by reaction of the parent sulphides with either XeF2 [147], an N–F-type reagent [148], or anodic fluorination in Et3 N3HF as the electrolytic medium [149, 150]. A Pummerer-type mechanism has been proposed (Figure 3.21a). F

F S R

−H

S CH3

R

CH3

S R

H C

S H

R

CH2F

Figure 3.21a

Similarly, a-fluoro sulphoxides are prepared by fluorination using DAST [151].

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Chapter 3

Remarkably, iodine pentafluoride in Et3 N3HF acts, in some cases, like an electrophilic fluorinating agent, replacing C2H in preference to oxygen functions [152] (Figure 3.21b). COCH2SEt

COCF2SEt i, ii

+ IF5 F

½152


F

F

F 82%

i, iii CH3COCH2COOEt + IF5

CH3COCHFCOOEt 71%

i, ii, iii,

Et3N.3HF heptane 74
C heptane 40
C

Figure 3.21b

IV

FLUORINATION OF OXYGEN-CONTAINING FUNCTIONAL GROUPS

A Replacement of hydroxyl groups by fluorine 1 Pyridinium poly(hydrogen fluoride) – Olah’s reagent The low boiling point and the health hazard associated with anhydrous hydrogen fluoride makes it very difficult to handle in the laboratory, even though it is used extensively by industry. Various amine/hydrogen fluoride complexes, which are markedly less volatile and less acidic than hydrogen fluoride, have been prepared and used as fluorinating agents [15, 153]. The most commonly used base/HF systems are triethylamine tris(hydrogenfluoride) and pyridinium poly(hydrogenfluoride) (PPHF, Olah’s reagent). Secondary and tertiary alcohols can be converted to the corresponding fluorides by reaction with pyridineðHFÞn [43] (Figure 3.22). Preferential fluorination of tertiary alcohols over OH

F

i

99% i, Pyridine.(HF)n, 20
C, 2 hr

F

OH

i

i, Pyridine.(HF)n, 20
C, 1 hr

Figure 3.22

95%

½43


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Partial or Selective Fluorination

63

secondary hydroxyl groups is possible, due to the much higher reactivity of tertiary hydroxyl groups towards pyridineðHFÞn [154] (Figure 3.23). ½154


i OH

F

O

O

HO

HO i, Pyridine.(HF)n, −35
C, CH2H2

Figure 3.23

Proton SpongeHF (Figure 3.24) is a particularly useful system which is an effective fluoride-ion donor for appropriate fluorinations [38, 155]; it is likely that the proton in this system is much less involved in H-bonding to fluoride than is the proton in hydrogen fluoride. H Me2N

NMe2

½38


Proton Sponge. HF (PS.HF) F

PS.HF

i

CF2CFCF3

+

(CF3)2CF

C3F6

C2F3

F3C

F 72%

i, CH3CN, rt

H

F3C

H N Cl

i

N

N F

+

PS.HCl

N 79% i, PS.HF, CH3CN, rt

Figure 3.24

A combination of IF5 with Et3 N3HF appears to be effective in replacing hydroxyl [152] (Figure 3.25).

2

Diethylaminosulphur trifluoride (DAST) and related reagents [156–158]

DAST was first used as an alternative fluorinating agent to sulphur tetrafluoride, by Middleton [159]. Although DAST, prepared by the reaction of SF4 with diethylaminotrimethylsilane [160] (Figure 3.26), can be used in normal laboratory glassware at

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64

Chapter 3 p-CH3-C6H4-CH2OH i, ii,

i, ii

+ IF5

p-CH3-C6H4-CH2F

½152


83%

Et3N.3HF CH2Cl2

Figure 3.25 Et2NSF3 + Me3SiF

SF4 + Et2NSiMe3

½159


DAST

Figure 3.26

atmospheric pressure, care must be exercised since it may decompose violently above 508 C [161]. Consequently, more stable analogues such as the morpholino [162] and piperidino derivatives have been used and a methoxyethyl derivative has become commercially available, MeOCH2 CH2 Þ2 NSF3 (Deoxo-Fluort, Air Products Company) [163]. Primary, secondary, tertiary and allylic hydroxyl groups are replaced by fluorine in excellent yields [12, 164] via a process involving an intermediate alkoxysulphur difluoride, the presence of which is supported by both spectroscopic [165] and chemical evidence [166] (Figure 3.27). ROH

+

Et2NSF3

ROSF2NEt2

F

RF

+

FSONEt2

½165, 166


Figure 3.27

For most substrates SN 2 replacement of hydroxyl by fluorine occurs with complete inversion of configuration [12] although retention of stereochemistry is observed when neighbouring groups containing either C5C double bonds, oxygen or nitrogen become involved in the reaction centre [17]. Allylic alcohols may be converted to mixtures of isomeric allyl fluorides by either an SN i or SN 20 process [12] (Figure 3.28). F F S

NEt2

½12


O R

SNi

F F NEt2 F S O R F

Figure 3.28

SN2'

R

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Partial or Selective Fluorination

65

Table 3.5 Replacement of hydroxyl groups by fluorine Substrate

Reagents/Conditions

n-C8 H17 OH

DAST CH2 Cl2 , 708 C to rt

PhCH2 CH2 OH

Deoxo-Fluort CH2 Cl2 , rt, 16 h

Yield (%)

Ref.

n-C8 H17 -F

90

[159]

PhCH2 CH2 F

85

[163]

71

[167]

53

[168]

F

HO

DAST CH2 Cl2 , 408 C to rt

O

F HO HO

O

O

SPh

O

F HO HO

OMe

Et2 OÞ2 POCHðOHÞPh H3C

Product

DAST CH2 Cl2 , rt DAST CH2 Cl2 , 08 C

OMe

Et2 OÞ2 POCHFPh H3C

OH O

O

F

[169] O

SPh O

Such is the versatility of DAST and related reagents that many fluorinated derivatives of natural products, including steroids, carbohydrates, nucleosides, prostaglandins and vitamin D analogues, amongst others, have been successfully synthesised [10, 16, 17] (Table 3.5). Generally, sulphur tetrafluoride can only be used for fluorodehydroxylations of acidic alcohols, otherwise extensive decomposition to side-products predominates. However, b-fluoroamino acids can be prepared by such a process [7].

3

Fluoroalkylamine reagents (FARs) [170]

Fluoroalkylamine reagents (FARs) such as the Yarovenko reagent [171], Et2 NCF2 CFClH, and Ishikawa’s reagent [172], Et2 NCF2 CFHCF3 , have been used to fluorinate alcohols, carboxylic acids and hydroxyamino acids [173–175] (Figure 3.29), most probably by a process outlined in Figure 3.30. More recently, the adduct to tetrafluoroethene, Me2 NCF2 CF2 H, has been shown to be a viable alternative reagent [176]. Enantio-controlled processes have been developed [177]; polymer-supported [178] FARs and other related systems such as PhCF2 2NMe2 have also been studied [179], and reactions in supercritical carbon dioxide have been reported [180]. 2,2-Difluoro-1,3-dimethylimidazoline (DFI) has recently been prepared and is very useful for replacing OH in alcohols by F. Carbonyl is converted to CF2 with accompanying elimination in some cases, whereas carboxyl is not converted to CF3 [181] (Figure 3.31).

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Chapter 3

O

O

½173175


i

HO

F

57%

i, Et2NCF2CFClH, CH2Cl2

O

O i HO

F

OMe

45%

OMe

i, Et2NCF2CFHCF3, CH2Cl2, 18 hr

Figure 3.29 F

Et N Et

C

CFHCF3

−F

F

Et N

C

CFHCF3

N

Et

F

F

Et Et

CFHCF3

O R

O R

C

H

H −H

Et

Et N Et

C

N

CFHCF3 Et

O

C

CFHCF3

−F

F

Et N Et

O R

+

R

F

C

CFHCF3

O R

F

Figure 3.30

B Replacement of ester and related groups by fluorine Fluoride-ion substitution of an acetyl group has, generally, been limited to the preparation of glycosyl fluorides [182] (Figure 3.32). However, displacement of sulphur ester groups such as tosylate [183], mesylate [184] and triflate [185] groups are of much greater synthetic importance. These excellent leaving groups are readily displaced by an active source of fluoride ion; this process represents an efficient method for the overall transformation of hydroxyl groups to fluorinated derivatives (Figure 3.33).

C Fluorination of carbonyl and related compounds 1 Sulphur tetrafluoride and derivatives Sulphur tetrafluoride, a colourless gas (b.p. 388 C) with toxicity of the same order as phosgene, has been commercially available since a practical method for its synthesis was

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Partial or Selective Fluorination

N

COCl2

N

N

Me

Me

KF

N Me

Me

O

N

N

F

F

½181
Me

Me

Cl

67

Cl DFI

i, ii

n-C8H17OH

i, iii p-HOC6H4-NO2 O

n-C8H17F

87%

p-FC6H4-NO2

62%

F

F

F

i, iv

i, DFI ii, CH3CN, 25
C iii, CH3CN, 85
C iv, Glyme, 85
C

21%

72%

Figure 3.31 O

AcO i

O

O

½182


AcO

O

OCOCH3 F O

O

O

O

i, HF, CH3NO2, Ac2O, 0
C, 3 hr

Figure 3.32

developed [186, 187] (Figure 3.34), although it is difficult to purify [188]. Its most general function is to exchange C5O for CF2 and it is usefully applied to the conversion of aldehydes and ketones to the corresponding difluorides, and of carboxylic acids (via the acid fluoride) to trifluoromethyl derivatives. Many examples have been documented and reviewed [2, 7, 156, 189] (Figure 3.35). The observation that anhydrides are not as reactive as carboxylic acids led to the use of acid catalysts with sulphur tetrafluoride; reactions are frequently carried out in the presence of anhydrous hydrogen fluoride, while BF3 , AsF3 , PF5 and TiF4 are also potent catalysts [190]. Conversions can be achieved in the presence of a wide range of other functional groups, for example bromo, chloro and unsaturated functions, although under some circumstances halogen exchange occurs [191]. Exchange of C5O for CF2 occurs in many classes of carbonyl compounds [2, 7, 156, 189], such as amides, esters, 1,2-dicarbonyls, hydroxy ketones, lactones, acid halides, carboxylic acids, some quinones

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68

Chapter 3 i n-C8H17OSO2C6H4CH3

½183


59%

n-C8H17F

i, KF, PEG 400, 27hr, 50
C

F

OSO2CH3

i

OCH3

OCH3

83%: 96% e.e.

½184


O

O i, KF, HCONH2, 60
C, 20 torr O

O F

i

65%

OSO2CF3

Cl

½185


Cl

i, Bu4NF, THF, 4 hr

Figure 3.33 3 SCl2 3SCl2 +

+ 4 NaF

CH3CN, 70
C

SF4

4Py.(HF)n

SF4

+ +

S2Cl2

+

4 NaCl

90%

½186
½187


S2Cl2

Figure 3.34 C6H5CHO HOOCC

SF4, 150
C

CCOOH

C6H5CHF2

SF4, 170
C

CF3C

81%

CCF3

80%

Figure 3.35

and fluoroformates (Table 3.6). Quite reasonably, the mechanism has been formulated as in Figure 3.36 [190]. Conversion of benzene-1,3,5-tricarboxylic acid to the corresponding tris (trifluoromethyl) compound provided a new source of bulky ligands for the organometallic chemist [192] (Figure 3.37). The intervention of a radical process has been suggested to account for the anomalous reaction with anthrone, leading to exchange of hydrogen for fluorine rather than attack at the carbonyl group [193] (Figure 3.38). Aminosulphur trifluorides, which are easier to handle than SF4 , can also be used for the conversion of most aldehydes and ketones to difluoromethylene derivatives; numerous examples have been documented [12] (Table 3.6). A similar reaction mechanism to that for SF4 may be assumed. Molybdenum hexafluoride [201], chlorine monofluoride [49] and phenylsulphur trifluoride [202] have all been used to perform similar transformations in a limited number of cases.

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 69

Partial or Selective Fluorination

C

C

δ C

XFn

O

δ O

C

F

O

F

F + SOF2 + XFn

F

δ C

SF4

XFn

δ O

½190


XFn

F

SF3

SF2

C

O

F

F

XFn−1

69

+

SF3

XFn

XFn = Lewis Acid

Figure 3.36 COOH

CF3

CF3

Li etc HOOC

COOH

F3C

CF3

F3C

½192


CF3

Figure 3.37 O

O i

i, SF4, HF, CH2Cl2

82%

F

½193


F

Figure 3.38

D

Cleavage of ethers and epoxides [157]

The reaction between epoxides and HF gives fluorohydrins and, generally, other products resulting from extensive polymerisation. However, the acidity and reactivity of HF may be decreased by the addition of a base, either an amine or KF, or by complexation with a Lewis acid, such as borontrifluoride etherate [174]. Consequently, pyridineHF, Et3 N3HF [203] and i-Pr2 NH3HF [204] efficiently cleave epoxides to give excellent yields of fluorohydrins (Figure 3.39). F

O

H H

i-Pr2NH.HF

½204


OH

Figure 3.39

The regioselectivity of the reaction is dependent on the hydrofluorinating reagent used. PyridineðHFÞn is highly acidic and the reaction proceeds by protonation of the ring oxygen, followed by fluoride ion attack on the carbon atom upon which the developing

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70

Chapter 3

Table 3.6 Fluorination of carbonyl and related groups Substrate

Reagent, conditions

C6 H5 CHO C6 H5 CHO

SF4 , 1508 C, 6 h Deoxo-Fluort, rt

O

Yield (%)

Ref.

C6 H5 CF2 H C6 H5 CF2 H

81 95

[194] [163]

O

F

O

SF4 , 1308 C O

Product

O

F

[195]

F

F

O

CO2H

CF3

SF4 , 1008 C N

25

[196]

76

[197]

18

[198]

45

[199]

82

[200]

N

CO2H

CF3

F

CO2H

SF4 , HF, 2008 C

F O

CO2H CF3

CO2H HO2C

F3C

CO2H

F

F

CF3

SF4 , HF, 1408 C HO2C O H

CF3

F3C

CO2H

HF2C O

O

OMe

OMe

DAST, CH2 Cl2 , rt O O

C6 H5 COCH2 F

O

O

DAST, benzene, 508 C

C6 H5 CF2 CH2 F

positive charge is most readily stabilised. Conversely, i-Pr2 NH3HF is not sufficiently acidic to protonate the ring oxygen significantly and so ring opening occurs by fluorideion attack at the least hindered carbon atom in an SN 2 process [205] (Figure 3.40). Larger oxygen-containing rings can also be cleaved [206] (Figure 3.41). Recently, silicon tetrafluoride [207] and tetrabutylphosphonium fluoride [208] have been used to prepare fluorohydrins from epoxides. Generation of a superacid is required for the ring opening of a perfluorinated oxirane [209] (Figure 3.42). Silyl ethers may be cleaved by either Bu4 NF=CH3 SO2 F [210] or ArPF4 [211] to give alkyl fluorides. Fluoroformates decarboxylate, on heating in the presence of an acid catalyst, to give the corresponding fluoride [212, 213] (Figure 3.43).

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Partial or Selective Fluorination OH

O

F

71

½205


+ OBu

OBu

OBu

F Reagent : i-Pr2N.3HF Pyridine.HF

OH

Ratio : 6 1

1 4

Yield,

81% 68%

Figure 3.40 F

F CF3

HF, 95
C

½206


O F

COF

F

Figure 3.41 F

O

CF3

F

i

(CF3)3COH

56%

½209


CF3 i, HF, SbF5, 100
C

Figure 3.42 OCOF

F

½212, 213


i

i, AlF3, HF, 200−300
C

Me

OCOF Me

F Me

Me

i

i, HF, 130
C

½214
69-75%

Figure 3.43

V

FLUORINATION OF SULPHUR-CONTAINING FUNCTIONAL GROUPS

Several methods concerning the formation of CF, CF2 and CF3 groups by fluorodesulphurisation [215, 216] processes have been reported (Table 3.7). Generally, these fluorinations are achieved by first activating the C2S or C5S bonds by complexation of the sulphur atom with a thiophilic reagent, such as an iodonium-ion source, followed by nucleophilic attack at the carbon atom, now a site of developing positive charge, by fluoride ion (Figure 3.44).

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72

Chapter 3

Table 3.7 Fluorodesulphurisation reactions Substrate

Reagents/Conditions

Product

Yield (%)

Ref.

BnO

BnO

p-MeC6 H4 -IF2 O

BnO BnO

CH2 Cl2 ,  788 C to rt BnO

S

F BnO

S-Ar

S

[217]

O

BnO BnO

CF2CF3

PyridineðHFÞn , NBSa

CF3 78 C to rt

[218] n-Pr

n-Pr CF2Ph S

S Ph

F2 , I2 , CH3 CN, rt

[219]

Br

Br CF2H S

S

C6H11

H

BrF3

70

S

S Me

F

O

O

DASTb , CH2 Cl2 , rt

C(SEt)3

PyridineðHFÞn , NBS

S SEt

[223]

PhCH2 SMe

a b

S

CF3

BrF3 , 08 C

PhCH2 N

[222]

S Br

Br

[221]

CF3

788 C to rt

S

MeO

[220]

Bu4 N þ H2 F 3

N CF3

NBS, rt

NBS, N-bromosuccinimide. DAST, diethylaminosulphur trifluoride.

MeO

[224]

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Partial or Selective Fluorination

73

I C

S

I

R

C

S

C

R

F

F

Figure 3.44

More recently, dithionylium salts (3.45A) have been explored for reactions with diols, amines and even azide [225], in the presence of fluoride sources, and an electrophilic brominating agent 5,5-dimethylhydantoin (DBH) to effect desulphurisation. High yields are obtained under very mild conditions (Figure 3.45). S

i-iv

R

RCF2N3

CF3SO3 S

½225


89% 3.45A

i, Me3SiN3, CH2Cl2, 0
C ii, Bu4NF, THF, 0
C iii, Et3N.3HF iv, DBH

Figure 3.45

VI A

FLUORINATION OF NITROGEN-CONTAINING FUNCTIONAL GROUPS Fluorodediazotisation [226]

In the classic Balz–Schiemann reaction [227, 228], arylamines are converted to fluoroaromatics via the corresponding diazonium tetrafluoroborate salts. The leaving group, molecular nitrogen, is lost on pyrolysis and the mechanism appears to involve formation of an aryl cation, which then abstracts fluoride ion from the tetrafluoroborate counter-ion (Figure 3.46). Variations of this procedure include the use of nitrite esters [229] as alternative nitrosating agents and the decomposition of hexafluorophosphate [230] and hexafluoroantimonate [231] diazonium salts. Photolysis [232], rather than pyrolysis, has been successfully used for the decomposition stage. When anhydrous HF, or the less volatile pyridineðHFÞn , is used as the reaction medium, isolation of the intermediate is unnecessary because decomposition of the diazonium salt occurs in situ. Many fluorinated aromatics can be prepared (Table 3.8) and, indeed, fluorobenzene is manufactured on a multi-ton scale using this methodology. Benefits arising from the use of ionic liquids have been claimed [233]. ArNH2

i, ii

i, HCl, NaNO2 ii, HBF4

Figure 3.46

ArN2

BF4

heat

ArF

½227, 228


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 74

74

Chapter 3 HO R

COOH

R O

R

O

H

R

COOH

F

H

½234


H H2N

H

N2

H O (HF)nF

Figure 3.47

By a similar process, amino acids have been converted to a-fluorocarboxylic acids by fluorodediazotisation processes [234] and, generally, retention of configuration is observed due to neighbouring group participation of the adjacent carboxyl group (Figure 3.47 and Table 3.8).

B Ring opening of azirines and aziridines Aziridines may be ring-opened regioselectively by either HF or amineHF mixtures to give b-fluoroamine derivatives [239, 240]. The mechanism, either SN 1 or SN 2, and consequently the stereochemical outcome of the reaction are greatly influenced by the precise nature of both the aziridine and the fluorinating agent used. For example, phenylsubstituted aziridines can be considered to react via the most stable carbocation in an SN 1 process, which accounts for the mixture of stereoisomers obtained [239] (Figure 3.48). 1-Azirines also may be ring-opened in a similar manner [241]. Table 3.8 Fluorodediazotisation Substrate

Reagents/Conditions

Me NH2

Product

Yield (%)

Ref.

Me

i, NaNO2 , HCl ii, HBF4 iii, Heat

F

Me

[235]

Me

H2N

CO2Et

N

i, NaNO2 , HBF4 ii, hn, HBF4 ,  508 C

F

CO2Et

N

NH

39

[236]

93

[237]

76

[238]

NH F

NH2

NaNO2 , pyridineHF N

N H3C

COOH

H2N

H

NaNO2 , pyridineHF

R

COOH

F

H

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Partial or Selective Fluorination

H

H N

H

H

Ph

H

H2 N

Ph

Me

H

H

Me

Ph

NH2

75

½239


Me

F

NH2

F Ph H

NH2

F +

Me

H Ph

Me 8%

69%

Figure 3.48

C

Miscellaneous

Nucleophilic substitution of nitro [242, 243] and trimethylammonium groups [244] by fluoride ion has been employed for the preparation of a number of fluoroaliphatic and fluoroaromatic substrates (Figure 3.49). KF, sulpholan

(NO2)3CF

(NO2)2CF2

NO2

59%

½242, 243


70%

½242, 243


NO2 i NO2

F

i, Me4NF, DMSO, 100
C, 4 hr 18F

N(CH3)3 i

91%

ClO4

½244


NO2

NO2 i,

Cs18F,

DMSO, 120
C

Figure 3.49

Hydrazones can be converted into gem-difluorides upon reaction with either fluorine [245], bromine monofluoride (generated in situ) [246] or ‘iodine monofluoride’ [247], and the reaction of diazoketones with fluorine results in similar transformations [248] (Figure 3.50).

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76

Chapter 3

O

O

EtO

O

i OEt

O 70%

EtO F

N2

½248


OEt F

i, F2, CFCl3, −70
C

i

CH3

60%

½246


CF2CH3 NNH2 i, Pyridine.(HF)n, NBS, CH2Cl2

‘IF’ CH3

80%

½247


CF2CH3

NNH2

Figure 3.50

VII

ADDITIONS TO ALKENES AND ALKYNES [249]

A Addition of hydrogen fluoride Addition of hydrogen fluoride to alkenes proceeds, as might be expected, via trans addition in a typical Markovnikov process, with the complicating effect of cationic polymerisation of the alkenes [250] (see also Chapter 7). However, side-products resulting from polymerisation of the alkene may be reduced by performing the reaction in a lower-acidity amineHF mixture [43] (Figure 3.51). CH3CHCH2

HF, −45
C

CH3CHFCH3

62%

i F

65%

½250


½43


i, Pyridine.(HF)n, THF, 0
C

Figure 3.51

Reactions with less nucleophilic, halogenated alkenes require more vigorous conditions and a Lewis acid catalyst is generally added to prepare commercially significant fluorohaloalkanes [251, 252] (Figure 3.52). Addition to acetylenes occurs under a variety of conditions; the reaction of acetylene with hydrogen fluoride is important for the manufacture of vinyl fluoride, although the

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 77

Partial or Selective Fluorination CHClCCl2

HF, TaF5

CF2CHCl

BF3, 25
C

CH2ClCCl2F

CF3CH2Cl

HF

77

½251, 252


89%

90%

Figure 3.52

addition proceeds further to give some difluoroethane [253]. With pyridineHF the reaction goes via the expected intermediate fluoroalkene to give difluoroalkanes only [43] (Figure 3.53). i C4H9C

C4H9CF2CH3

CH

70%

½43


i, Pyridine.(HF)n, THF, 0
C

Figure 3.53

The addition of hydrogen fluoride to electron-deficient alkenes and alkynes can be achieved in certain cases via an indirect process in which reaction of the alkene or alkyne with fluoride ion leads to a carbanion that abstracts a proton from the solvent. This method, however, is limited to cases where other reactions of the carbanion are hindered or less favourable [254, 255] (Figure 3.54). F

F CF3

i O

C6H5

C6H5

O

OR

OR

71%

½254


R = methyl

i, Bu4NF, THF, 0
C, MeC6H4SO3H

F

i MeOOCC

CO2Me

CCOOMe MeO2C i, Bu4NH2F3, CH2Cl

H

90%

½255


CH2Cl, 60
C

Figure 3.54

Hydrofluorination of corresponding C5N bonds of isocyanates and diazoketones gives carbamyl fluorides and a-fluoroketones repectively [43].

B

Direct addition of fluorine

It was first shown that the addition of fluorine to haloalkenes can be controlled if the temperature is lowered, competition between fluorine addition and dimer formation being dependent on the conditions [256] (Figure 3.55). Russian workers subsequently reported controlled addition to vinyl acetate [257] and fumaric acid [258], to give difluoroethyl acetate and monofluoroacetaldehyde, respectively. Selective fluorination of many alkanes [8, 259], such as acenaphthene [260],

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78

Chapter 3 CF3CF=CFCF3

F2, −75
C

CF3CF2CF2CF3

+ [CF3CF2CF(CF3)]2

½256


CFCl3

Figure 3.55

1,1-diphenylethene [261] and many steroids [236], is now possible in sometimes surprisingly high yield by passing fluorine diluted with an inert gas through a solution of the unsaturated compound (Table 3.9). Table 3.9 Direct fluorination of alkenes Substrate

Reagent, conditions O

Product

F

O F

O N Boc AcO

F2 , N2 CFCl3 , CHCl3 , EtOH 788 C

O

[259]

65

[237]

41

[262]

40

[263]

F

F

O

F

N Boc

AcO

O

F

F

AcO OAc

35 F

F2 , Ar CFCl3 , 788 C AcO

Ref.

O

F2 , N2 CFCl3 , CHCl3 , EtOH 758 C

O

Yield (%)

OAc

Unlike other halogenation reactions, direct fluorinations of alkenes give products resulting predominantly from syn addition, and a mechanism suggesting a four-centred intermediate formed by a concerted pathway was first proposed to account for this [238]. Further experimental [259] and theoretical work [235] provide evidence for an electrophilic mechanism involving a tight ion-pair (3.56A) as an intermediate. Collapse of this ion-pair 3.56A gives the syn-1,2-difluoride, whilst loss of a proton forms a fluoroalkene which may then undergo further fluorination to yield a trifluoride (Figure 3.56). Three products are observed in the fluorination of 1,1-diphenylethene [238] (Figure 3.57). A carbocationic intermediate is further supported by observed rearrangements [236] (Figure 3.58).

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Partial or Selective Fluorination

79

F δ F

F

F H

F

δ

F H

F

F

½235, 259


H

H 3.56A −H

F

F F

F

F2

Figure 3.56 Ph2CCH2

F2, N2

Ph2CFCH2F 14%

+

Ph2CCHF 78%

+

Ph2CFCF2H 8%

½238


Figure 3.57 O

O

½236
F2, N2

AcO

Cl

F

Cl

O F F F

O F

Figure 3.58

C

Indirect addition of fluorine

Reaction of alkenes with an electrophilic fluorinating agent such as caesium fluoroxysulphate, in the presence of fluoride ion, can result in addition of fluorine to the double bond [264] (Figure 3.59). Carbocationic species are also considered to be intermediates in reactions between iodobenzene difluoride and alkenes [265, 266]. Tetrafluorination of alkynes is possible using nitrosonium tetrafluoroborate and pyridineðHFÞn [267] (Figure 3.60).

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80

Chapter 3 Ph

Ph H F

i Ph

F H Ph

syn:anti 65 : 35

½264


i, CsSO3OF, HF, CH2Cl2, 20
C

Figure 3.59 i PhC

CPh

75%

PhCF2CF2Ph

½267


i, NO BF4, Pyridine.(HF)n

Figure 3.60

Of course, most reactive metal fluorides, such as cobalt trifluoride [268] and vanadium pentafluoride, will react with alkenes but the reactions can be very difficult to control, except for haloalkenes [269]. Much easier control is possible with xenon fluorides [137], the reactivity decreasing in the series XeF6 > XeF4 > XeF2 . Since the first report of the use of xenon difluoride for the addition of fluorine to double bonds, many studies have been published and reviewed [54, 135] (Figure 3.61). PhCHCHPh

+

XeF2

HF, CH2Cl2

cis trans

PhCHFCHFPh

½270


90%

erythreo:threo = 53 : 47 62 : 38

+ XeF2

HF, CH2Cl2

F

+

F

F

F 87

13

Figure 3.61

The reaction is non-stereoselective, contrary to direct fluorination, and it is found that only slight changes in either the reaction conditions or the structure of the substrate can give rise to differing amounts of syn or anti addition. The addition of a Lewis acid, usually HF [270] or BF3 Et2 O [271], to the reaction mixture gives much higher yields of the desired difluoroalkanes, and both ionic and single-electron transfer pathways have been suggested [272, 273]. The very reactive species PbðOCOCH3 Þ2 F2 , formed in situ by the reaction of lead tetraacetate with hydrogen fluoride [274], has been used very effectively for adding fluorine to alkenes, especially in the synthesis of the biologically important 6a-fluoro steroidal hormones [275].

D Halofluorination The combination of a source of electrophilic halogen together with a fluoride ion reagent permits efficient halofluorination of nucleophilic carbon–carbon double bonds; products resulting from addition in a trans stereochemistry are usually obtained (Figure 3.62).

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 81

Partial or Selective Fluorination Hal

Hal

81

Hal

F F

Figure 3.62

A wide variety of reagent systems have been developed to carry out this synthetically useful reaction (Table 3.10). The intermediate halonium ion may undergo well-established carbocationic rearrangements, for instance in the halofluorination of norbornadiene [276] (Figure 3.63). The reaction has been used extensively for the introduction of fluorine into steroids [277], where a curious anomaly arises between BrF and IF addition. As indicated, stereospecific anti addition occurs in most reactions but syn addition of BrF or IF to carbohydrates has been observed [278]. Halofluorination of alkynes proceeds as expected, although further reaction of the resulting alkene derivative can occur. Table 3.10

Halofluorination of alkenes and alkynes

Substrate

Reagent/Conditions

Product

a

F

NIS , pyridineHF

Yield (%)

Ref.

65

[43]

87 (9:1)

[279]

60

[280]

85

[43]

I C4H9

DBH b, KF2H2 O H2 SO4 , CH2 Cl2

C4H9

Br F +

C4H9

F Br

Me

Me N

I

− BF4

F I

2

CH2 Cl2 , 08 C F

Br2 , AgNO3 pyridineHF Br a b

NIS, N-iodosuccinimide. DBH, 1,3-dibromo-5,5-dimethylhydantoin.

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82

Chapter 3

i Br

½276


53%

F

i, NBS, Et3N.3HF, CH2Cl2, 0
C 38%

Br F

5%

Br Br

Figure 3.63

E

Addition of fluorine and oxygen groups

Evidence has been presented that hypofluorites (see Section IIIB) can act as sources of electrophilic fluorine for reactions with electron-rich double bonds [11, 93]. Syn addition usually occurs and a tight ion-pair intermediate similar to that postulated to occur in the direct fluorination of alkenes can be envisaged. However, electron-transfer processes have been invoked [93] to explain some anomalous results and cannot be discounted [281] (Figure 3.64). H3C

H3C

H3C O

i

AcO

Y

AcO

AcO i, CF3OF, CFCl3, −70
C

AcO

½281


O

O

X

X=F, Y=OCF3, 31% X=Y=F, 22%

+

AcO

Y AcO

X

X=F, Y=OCF3, 11% X=Y=F, 12%

Figure 3.64

Additions of hypofluorites to unsaturated sites have been performed [17] on a wide variety of substrates [282, 283] (Figure 3.65). CsSO3 OF reacts with alkenes to give fluoroalkyl sulphates [284].

F Other additions In a similar process to halofluorination, sulphur- [285], selenium- [286] and nitrogencontaining [43] groups and fluorine may be added to hydrocarbon double bonds by reaction of an alkene with an electrophilic reagent of the heteroatom species in conjunction with a fluoride-ion source (Figure 3.66). As expected, Markovnikov addition in trans stereochemistry occurs mainly.

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 83

Partial or Selective Fluorination

83

F

½282


OMe i

40%

i, CH3OF, CH3OH, CH3CN, −40
C

OAc

OAc

½283


i AcO

AcO

F

OCF3

i, CF3OF, CFCl3, −75
C

59%

Figure 3.65 Ph

SCH3

Ph H F

i CH3

H CH3

½285


90%

−

i, (CH3)2SSCH3 BF4 , Et3N.3HF, CH2Cl2, rt

SePh

i F

MeO

MeO

½286
53%

i, PhSeCl, AgF, CH3CN F i 65%

½43


NO2 i, NO2BF4, Pyridine.HF, 0
C

Figure 3.66

REFERENCES 1 2 3 4 5 6 7 8

W.A. Sheppard, Org. Reactions, 1974, 21, 125. G.A. Boswell, W.C. Ripka, R.M. Scribner and C.W. Tullock, Org. Reactions, 1974, 21, 1. M. Schlosser, Tetrahedron, 1978, 34, 3. M.R.C. Gerstenberger and A. Haas, Angew. Chem., Int. Ed. Engl., 1981, 20, 647. S. Rozen and R. Filler, Tetrahedron, 1985, 41, 1111. A. Haas and M. Lieb, Chimia, 1985, 39, 134. C.J. Wang, Org. Reactions, 1985, 34, 319. S.T. Purrington, B.S. Kagen and T.B. Patrick, Chem. Rev., 1986, 86, 997.

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84

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50

Chapter 3

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H. Suga, T. Hamatani and M. Schlosser, Tetrahedron, 1990, 46, 4247. M. Muehlbacher and C.D. Poulter, J. Org. Chem., 1988, 53, 1026. W. Dmowski and R.A. Kolinski, Pol. J. Chem., 1974, 48, 1697. M. Shimizu and H. Yoshioka, Tetrahedron Lett., 1989, 30, 967. H. Seto, Z.H. Qian, H. Yoshioka, Y. Uchibori and M. Umeno, Chem. Lett., 1991, 1185. F.J. Pavlic and P.E. Toren, J. Org. Chem., 1970, 35, 2054. M. Shimizu, Y. Nakahara and H. Yoshioka, Tetrahedron Lett., 1985, 26, 4207. D.U. Robert, G.N. Flatau, A. Cambon and J.G. Reiss, Tetrahedron, 1973, 29, 1877. G.A. Olah and S.J. Kuhn, J. Org. Chem., 1956, 21, 1319. H. Garcia, M.C. Perrod, L. Gilbert, S. Ratton and C. Rochin, J. Fluorine Chem., 1991, 54, 117. N. Lui, A. Marhold and D. Bielefeldt, Germ. Pat. 422 576 (1994); Chem. Abstr., 1994, 120, 216933a. J. Kollonitsch, S. Marburg and L.M. Perkins, J. Org. Chem., 1976, 41, 3107. M. Kuroboshi and T. Hiyama, J. Synth. Org. Chem. Jpn., 1993, 51, 1124. S. Caddick, W.B. Motherwell and J.A. Wilkinson, J. Chem. Soc., Chem. Commun., 1991, 674. M. Kuroboshi and T. Hiyama, J. Fluorine Chem., 1994, 69, 127. R.D. Chambers, G. Sandford and M. Atherton, J. Chem. Soc., Chem. Commun., 1995, 177. R. Sasson, A. Hagooly and S. Rozen, Org. Lett., 2003, 5, 769. W.H. Bunnelle, B.R. McKinnis and B.A. Narayanan, J. Org. Chem., 1990, 55, 768. D.P. Matthews, J.P. Whitten and J.R. McCarthy, Tetrahedron Lett., 1986, 27, 4861. S. Rozen and E. Mishani, J. Chem. Soc., Chem. Commun., 1994, 2081. M. Kuroboshi and T. Hiyama, Tetrahedron Lett., 1992, 33, 4177. P. Kirsch and A. Taugerbeck, Eur. J. Org. Chem., 2002, 3923. B. Langlois in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorine Compounds, ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 686. A. Roe, Org. Reactions, 1949, 5, 193. H. Suschitsky, Adv. Fluorine Chem., 1965, 4, 1. H. Diehl, H. Pelster and H. Habetz, Germ. Pat. 3 141 659 A1 (1983); Chem. Abstr., 1983, 99, 70360k. K.G. Rutherford, W. Redmond and J. Rigamonti, J. Org. Chem., 1961, 26, 5149. C. Sellers and H. Suschitzky, J. Chem. Soc. (C), 1968, 2317. K. Takahashi, K.L. Kirk and L.A. Cohen, J. Org. Chem., 1984, 49, 1951. K.K. Laali and V.J. Gettwert, J. Fluorine Chem., 2001, 107, 31. G.A. Olah, G.K.S. Prakash, and Y.L. Chao, Helv. Chim. Acta, 1981, 64, 2528. T. Iwaoka, C. Kaneko, A. Shigihara and H. Ichikawa, J. Phys. Org. Chem., 1993, 6, 195. D.H.R. Barton, J.L. James, R.H. Hesse, M.M. Pechet and S. Rozen, J. Chem. Soc., Perkin Trans. 1, 1982, 1105. R.F. Merritt and T.E. Stevens, J. Am. Chem. Soc., 1966, 88, 1822. R.F. Merritt, J. Org. Chem., 1966, 31, 3871. T.N. Wade, J. Org. Chem., 1980, 45, 5328. G.M. Alvernhe, C.M. Ennakoua, S.M. Lacombe and A.J. Laurent, J. Org. Chem., 1981, 46, 4938. T.N. Wade and R. Kheribet, J. Org. Chem., 1980, 45, 5333. M. Kamlet and H.G. Adolph, J. Org. Chem., 1968, 33, 3073. M. Boechat and J.H. Clark, J. Chem. Soc., Chem. Commun., 1993, 921. G. Angelini, M. Speranza, A.P. Wolf and C.-Y. Shiue, J. Fluorine Chem., 1985, 27, 177. T.B. Patrick and P.A. Flory, J. Fluorine Chem., 1984, 25, 157. G.K.S. Prakash, V.P. Reddy, X.Y. Li and G.A. Olah, Synlett, 1990, 594. S. Rozen and D. Zamir, J. Org. Chem., 1991, 56, 4695. T.B. Patrick, J.J. Schiebel and G.L. Cantrell, J. Org. Chem., 1981, 46, 3917.

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249 P. Wolfram in Houben-Weyl: Methods of Organic Chemistry, Vol. E10b/Part 1, Organofluorine Compounds, ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 308. 250 A.V. Grosse and C.B. Linn, J. Org. Chem., 1938, 3, 26. 251 A.L. Henne and R.C. Arnold, J. Am. Chem. Soc., 1948, 70, 758. 252 A.E. Feiring, J. Fluorine Chem., 1979, 14, 7. 253 F.W. Swarmer, US Pat. 2 830 100 (1958); Chem. Abstr., 1958, 52, 19943a. 254 T. Kitazume and T. Onogi, Synthesis, 1988, 614. 255 J. Cousseau and P. Albert, Bull. Chim. Soc. Fr., 1986, 910. 256 W.T. Miller, J.O. Stoffer, G. Fuller and A.C. Currie, J. Am. Chem. Soc., 1964, 86, 51. 257 A.Y. Yakubovich, S.M. Rozenshtein and V.A. Ginberg, USSR Pat. 162 825 (1965); Chem. Abstr., 1965, 62, 451g. 258 A.Y. Yakubovich, V.A. Ginsberg, S.M. Rozenshtein and S.M. Smirnov, USSR Pat. 165 162 (1965); Chem. Abstr., 1965, 62, 9018g. 259 S. Rozen and M. Brand, J. Org. Chem., 1986, 51, 3607. 260 R.F. Merritt and F.A. Johnson, J. Org. Chem., 1966, 31, 1859. 261 R.F. Merritt, J. Org. Chem., 1966, 31, 3871. 262 A. Toyota, M. Aizawa, C. Habutani, M. Katagiri and C. Kaneko, Tetrahedron, 1995, 51, 8783. 263 T. Ido, C.N. Wan, J.S. Fowler and A.P. Wolf, J. Org. Chem., 1977, 42, 2341. 264 S. Stavber and M. Zupan, J. Org. Chem., 1987, 52, 919. 265 W. Carpenter, J. Org. Chem., 1966, 31, 2688. 266 T.B. Patrick, J.J. Scheibel, W.E. Hall and Y.H. Lee, J. Org. Chem., 1980, 45, 4492. 267 C. York, G.K.S. Prakash and G.A. Olah, J. Org. Chem., 1994, 59, 6493. 268 A. Bergami and J. Burdon, J. Chem. Soc., Perkin Trans. 1, 1975, 2237. 269 G.G. Furin and V.V. Bardin in New Fluorinating Agents in Organic Synthesis, ed. L. German and S. Zemskov, Springer-Verlag, Berlin, 1989, p. 117. 270 M. Zupan and A. Pollak, Tetrahedron Lett., 1974, 1015. 271 S.A. Shackelford, R.R. McGuire and J.L. Pflug, Tetrahedron Lett., 1977, 363. 272 M. Zupan, M. Metelko and S. Stavber, J. Chem. Soc., Perkin Trans. 1, 1993, 2851. 273 S. Stavber, T. Sotler, M. Zupan and A. Popovic, J. Org. Chem., 1994, 59, 5891. 274 J. Bornstein, M.R. Borden, F. Nunes and H.I. Tarlin, J. Am. Chem. Soc., 1963, 85, 1609. 275 A. Bowers, P.G. Holton, E. Denot, M.C. Loza and R. Urquiza, J. Am. Chem. Soc., 1962, 85, 1050. 276 G. Alvernhe, D. Anker, A. Laurent, G. Haufe and C. Beguin, Tetrahedron, 1988, 44, 3551. 277 A. Bowers, E. Denot and R. Becerra, J. Am. Chem. Soc., 1960, 82, 4007. 278 K.R. Wood, P.W. Kent and D. Fisher, J. Chem. Soc., 1966, 912. 279 D.Y. Chi, D.O. Kiesewetter, J.A. Katzenellenbogen, M.R. Kilbourn and M.J. Welch, J. Fluorine Chem., 1986, 31, 99. 280 R.D. Evans and J.H. Schauble, Synthesis, 1987, 551. 281 G.C. Butchard and P.W. Kent, Tetrahedron, 1979, 35, 2439. 282 S. Rozen, O. Lerman, M. Kol and D. Hebel, J. Org. Chem., 1985, 50, 4753. 283 D.H.R. Barton, L.J. Danks, A.K. Ganguly, R.H. Hesse, G. Tarzia and M.M. Pechet, J. Chem. Soc., Perkin Trans. 1, 1976, 101. 284 N.S. Zefirov, V.V. Zhdankin, A.S. Kozmin, A.A. Fainzilberg, A.A. Gakh, B.I. Ugrak and S.V. Romaniko, Tetrahedron, 1988, 44, 6505. 285 G. Haufe, G. Alvernhe, D. Anker, A. Laurent and C. Saluzzo, Tetrahedron Lett., 1988, 29, 2311. 286 J.R. McCarthy, D.P. Matthews and C.L. Barney, Tetrahedron Lett., 1990, 31, 973.

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Chapter 4

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres

I

INTRODUCTION

Part of the interest in fluorocarbon systems lies in a comparison of the chemistry, and particularly reaction mechanisms, of fluorocarbon derivatives with those of the corresponding hydrocarbon compounds. Indeed, such comparisons pose quite a strenuous test on our theories of organic chemistry. As will be seen, our understanding of the influence of carbon–fluorine bonds on reaction mechanisms has made considerable progress. Nevertheless, it must be emphasised that fluorocarbon derivatives present much more complicated systems than their corresponding hydrocarbon compounds because, in addition to effects arising from different electronegativities, the effect of the lone pairs of electrons of fluorine that are not involved in s-bonds must be taken into consideration. Furthermore, the relative importance of these effects seems to be very dependent on the centre to which the fluorine is attached. In this chapter we assess the effect of fluorine on some charged and neutral systems largely at a qualitative level, where this effect can be relatively well defined. Indeed, it could be argued that models of reactivity that are to be useful over a variety of related reagents, in various concentrations and solvents, are by necessity only qualitative.

II

STERIC EFFECTS

Replacing hydrogen in an organic molecule by fluorine does not significantly alter the geometry of many systems, but this does not necessarily mean that fluorine and hydrogen ˚ , rv ðFÞ 1.47 A ˚ and are isosteric. A comparison of the van der Waals radii, rv ðHÞ 1.20 A ˚ rv (O) 1.52 A [1], suggests that fluorine is isosteric with oxygen, and this fact has long been recognised for the development of bioisosteric compounds in medicinal chemistry ˚ ) is slightly longer than C–H (1.09 A ˚ ); in very crowded [2]. The C–F bond length (1.38 A systems this can be significant. For example, phenyl ring rotation of the cyclophane system (Figure 4.1) is slower when X ¼ F than when X ¼ H, because of the larger steric requirement of fluorine over hydrogen [3]. Substituent steric effects are generally regarded in terms of Taft Es or Charlton n parameters [4], and a number of these values for fluorinated groups, along with those for some hydrocarbon groups, are listed in Table 4.1. These data suggest, for instance, that CF3 groups are much more sterically demanding than methyl substituents and that they Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

91

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½3


X

Figure 4.1

are more demanding than isopropyl groups. Indeed, van der Waals volumes, ˚ 3 compared to CF3 ¼ 42:6 A ˚ 3 , further illustrate this point [5] (Figure 4.2). CH3 ¼ 16:8 A ½5
H H

F H

F

16.8A3

F

42.6A3

Figure 4.2 Table 4.1

III

Steric parameters [4]

Substituent

Taft Es

Charton n

H F OH CH3 CH2 CH3 CHðCH3 Þ2 CðCH3 Þ3 CH2 F CHF2 CF3

þ1.24 þ0.78 þ0.69 0 0.07 0.47 1.54 0.24 0.67 1.16

0 — — 0.52 0.56 0.76 1.24 0.62 0.68 0.91

ELECTRONIC EFFECTS OF POLYFLUOROALKYL GROUPS [6]

In this section we will deal with the effects of a polyfluoroalkyl group as a whole attached to a saturated, and therefore not formally charged, carbon atom. The effect of fluorine and fluorinated groups directly bonded to reaction centres such as intermediate carbocation and carbanion sites will be treated in separate sections.

A Saturated systems 1 Strengths of acids As fluorine is the most electronegative element, it could be expected that the introduction of a fluorine atom or polyfluoroalkyl group into the carbon chain of an organic acid, such

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Table 4.2

93

pKa values of some organic acids and alcohols [7]

Carboxylic acid

pKa

Alcohol

pKa

CH3 COOH CH2 FCOOH CH2 ClCOOH CHF2 COOH CHCl2 COOH CF3 COOH CCl3 COOH CF3 CH2 CH2 COOH CF3 CH5CHCOOH

4.76 2.59 2.86 1.34 1.35 0.52 0.56 4.15 3.48

CH3 CH2 OH CF3 CH2 OH CCl3 CH2 OH ðCF3 Þ2 CHOH ðCH3 Þ3 COH ðCF3 Þ3 COH ðCHF2 Þ2 CðOHÞ2 ðCF3 Þ2 CðOHÞ2 ðCF3 Þ2 CðOHÞCF2 NO2

15.9 12.4 12.2 9.3 19.2 5.1 8.9 6.5 3.9

as an alcohol or carboxylic acid, would increase the acidity of the system and, indeed, this is the case. The pKa values [7] of a number of fluorine-containing acids, along with related systems for comparison, are collated in Table 4.2; these data suggest that the effect of introducing one fluorine atom is very close to that of a single chlorine atom (compare CH2 FCOOH and CH2 ClCOOH). A single fluorine substituent increases the acidity of acetic acid by ca. 100 times while trifluoroacetic acid is ca. 1000 times stronger. As expected, the inductive effect of trifluoromethyl falls off rapidly with distance, although the presence of a double bond helps to relay the effect. Various workers have drawn attention to the fact that, in aqueous solution, it is the entropy rather than the enthalpy that is more significant in determining the differences between the strengths of acids. This is a consequence of ordering of solvent which is greater as the acids become stronger. However, this is equally a consequence of inductive/field effects of groups. It is not surprising that, in the gas phase, acidities are determined by differences in enthalpies [8, 9]. It is still worth noting, however, that perfluoroalkanecarboxylic acids are much weaker than the strong inorganic acids: for example, the Hammett acidity function Ho for CF3 COOH is 3:03 while Ho for sulphuric acids is 11:1. The strong inductive effect of fluoroalkyl groups has a corresponding additive acidifying effect on alcohols (Table 4.2). For instance, perfluoro-t-butanol is of the same order of acidity as acetic acid. The hydrates of fluoroketones are also remarkably acidic [10]. Perfluoroalkyl groups attached to phosphorus and sulphur [11] lead to a considerable increase in the strength of derived acids, as compared with the corresponding alkyl derivatives. Bis(trifluoromethyl)phosphinic acid, CF3 Þ2 POOH, is as strong as perchloric acid and is the strongest phosphorus acid known [12], while trifluoromethanesulphonic (triflic) acid, CF3 SO3 H, is the strongest readily available monobasic organic acid (H0  13:8) (compare conc. H2 SO4 , H0 11:1).

2

Bases

Fluoroalkyl groups correspondingly lower the strengths of bases. Table 4.3 shows the dissociation constants of some amines, together with hydrocarbon derivatives for comparison.

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Table 4.3 pKb values of some amines Amine CH3 CH2 NH2 CF3 CH2 NH2 CCl3 CH2 NH2 C6 H5 NH2 C6 F5 NH2

pKb 10.6 5.7 5.4 4.6 0:36

The observations that secondary amines, RF Þ2 NH, do not react with boron trifluoride, hydrogen chloride or trifluoroacetic acid [13] also serve to indicate a lack of basic properties. Similarly, tertiary perfluoroalkylamines are quite without basic properties. Moreover, the oxygen atoms in perfluoroalkyl ethers and ketones are poor donors; this is exemplified by the fact that hexafluoroacetone cannot be protonated by superacids in solution. Such findings parallel similar observations with unsaturated derivatives where the base strength is considerably reduced in, for example, perfluoropyridine or perfluoroquinoline [14] in comparison with the parent compounds. The data, so far, clearly illustrate a very strong inductive effect (I) by polyfluoroalkyl groups in saturated systems, and the reduced donor properties of the hetero atom in nitrogen or oxygen derivatives probably partly arise from some rehybridisation (greater s character of orbitals containing the electrons not involved in s-bonds) when strongly electronegative substituents are attached [15].

B Unsaturated systems The deactivating effect and meta-orientating influence of trifluoromethyl in electrophilic aromatic substitution, together with a corresponding activating influence on nucleophilic aromatic substitution [16], are well known. Of course, these are just the results we would expect upon introducing a strongly electron-withdrawing group, but a more precise description of the mechanism of electron withdrawal by polyfluoroalkyl groups in these systems has been a source of debate. It has become normal to discuss the effects of substituents on benzene systems in terms of the Hammett equation, log k=k0 ¼ sr, where s measures the effect of a substituent on the reaction centre. Also, this simple concept has been elaborated, leading to correspondingly modified constants (s0 , sþ , s ) catering for the electronic nature of different reactions; some of the data relating to polyfluoroalkyl groups are contained in the following discussion (Table 4.4).

1 Apparent resonance effects (see also Section VIIB) The overall effect of substituents may be separated into inductive (sI ) and resonance (sR ) contributions, where s ¼ sI þ sR . Some of the data derived on this basis are given in Table 4.4: they indicate an apparent resonance contribution by various polyfluoroalkyl groups. The problem of describing such a resonance contribution then arises, and it is immediately tempting to draw an analogy with hydrocarbon systems and invoke ‘fluorine

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95

Table 4.4 Substituent constants for some fluorinated groups Substituent

sm

sp

sI

sR

CH2 F CHF2 CF3 CF2 CF3 CF2 Þ2 CF3 CFðCF3 Þ2 SF5 NðCF3 Þ2 OCF3

0.12 0.29 0.43 0.47 0.47 0.37 0.63 0.47 0.47

0.11 0.32 0.54 0.52 0.52 0.53 0.86 0.53 0.27

0.12 0.32 0.42 0.41 0.39 0.48 0.56 0.44 0.50

0.02 0.06 0.10 0.11 0.11 0.04 0.27 0.06 0.23

hyperconjugation’ or ‘carbon–fluorine double-bond no-bond resonance’. These are two terms which have been used to refer to an effect that was originally suggested [17] to account for the dipole moments of p-amino- and p-dimethylaminobenzotrifluoride, which are larger than the sums of the composite bond moments. The type of interaction that was envisaged is shown in Figure 4.3. F

F

F

F

C

F F

C

etc.

Figure 4.3

The concept of fluorine negative hyperconjugation (FNHC), which in its simplest form can be written as indicated in Figure 4.4, has had a controversial history although there can be little doubt about the firm theoretical requirement for such an effect [18–20]. Problems have arisen because there are few rate-constant measurements that require FNHC, in addition to inductive field effects, to account for the observations [21], although structural evidence for 4.5A and 4.5B (Figure 4.5) now illustrates the effect well [22, 23]. F

F C

C

C

C

Figure 4.4 CF3 −

CF3O

+

TAS

F

½22


− +

½23


TAS

F3C 4.5A

4.5B +

TAS

Figure 4.5

+

= (Me2N)3S

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In molecular orbital terms, the unshared p-electrons at the carbanion site are donated into the s orbital of the adjacent C–F bond when the orbitals are in an anti-periplanar configuration which ensures maximum orbital overlap [19, 20]. Trends in the C–F bond lengths and strengths in the fluoromethane series, in which the C–F bonds strengthen and shorten with increasing fluorination, have been explained in terms of resonance effects, but theoretical work suggests that Coulombic interactions and hybridisation changes could also explain these observations [24]. However, the unusually long C–F bond and short C–O bond measured for the trifluoromethoxide ion [22] (Figure 4.6) suggests that the C–O bond possesses some double-bond character and, similarly, the high barrier to rotation of a-fluoroamines indicates some C–N doublebond character [25]. F F C F

− F

− O

F C

O

½22


F

Figure 4.6

Stabilities of perfluorinated carbanions have also been described using FNHC; a reexamination [26, 27] of the acidity of CF3 Þ3 CH compared with the bicyclic compound (Figure 4.7), in which FNHC in the carbanion would result in the formation of an internal alkene contrary to Bredt’s rule, found that the unconstrained CF3 Þ3 CH undergoes H/D exchange much more rapidly. If FNHC is the dominant process involved, then we would expect sR for CF3 to be greater than for CF2 2CF3 but this is not the case (Table 4.4). Calculations suggest [28] that perfluoroalkyl negative hyperconjugation can also occur, as indicated in Figure 4.8, although this seems unlikely given the destabilising effect of fluorine directly attached to carbanion centres (Section VI).

−H+ F

F − H

Figure 4.7

− C

C

CF3

C

C

− CF3

Figure 4.8

Another probe technique that has been used is to compare the effects of trifluoromethyl, at the meta and para positions, in both phenol and benzoic acid [29]. Only in the case where the substituent is in the para position in phenol is it directly conjugated with the ionising centre and therefore allowing a resonance effect to be important. Values of pKa for the phenols led to the following substituent parameters: sð p-CF3 Þ ¼ þ0:54 and sðm-CF3 Þ ¼ þ0:43, the ratio sð p-CF3 Þ=sðm-CF3 Þ being 1.25, and this is essentially

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97

the same as the ratio for the corresponding trifluoromethylbenzoic acids. This suggests that the electronic effects of CF3 operating in the phenol system are the same as those operating in the benzoic acid system and not, therefore, in accord with a resonance effect. Also, other fluorinated groups have apparent resonance effects (Table 4.4) that would be difficult to defend on the basis of any negative hyperconjugation scheme. For many processes it is not really necessary to invoke the concept of fluorine hyperconjugation to account for the observations and the most easily appreciated description of many, but by no means all, of the results available involves polarisation of the p-electron system.

2

Inductive and field effects

It is generally recognised that the inductive effect should be subdivided into a polarisation effect on the s-bond framework and also on the p-electrons, and it has been indicated that a major effect of strongly electron-withdrawing groups like perfluoroalkyl is by a through-space polarisation of the aromatic p-electrons (direct field effect). The Ip effect of trifluoromethyl would result in polarisation of the p-system and perhaps approach a situation similar to that which exists in pyridine (Figure 4.9a). CF3 δδ+

CF3

δ+ δδ+

δ+

δ+

N

δ+

δ+

δ+

δ+

Figure 4.9a

This kind of description allows for a similar effect to be produced by other perfluoroalkyl groups (see Table 4.4), as well as the other fluorinated groups listed. Similar conclusions to those drawn here are described in a much more detailed review and analysis [30] of results available. Electrostatic interactions have been revealed as important in influencing the ‘gauche effect’, whereby, in 1,2-disubstituted ethanes (4.9bA), the gauche conformer (4.9bB) is populated to a larger extent than the anti conformer (4.9bC) [31, 31a] (Figure 4.9b). H H

H H

X

X H 4.9bA

H

Y

Y X

H

4.9bB

H Y 4.9bC

Figure 4.9b

IV

THE PERFLUOROALKYL EFFECT

Saturated, strained, small ring systems are uniquely stabilised by the introduction of perfluoroalkyl groups, as compared with the corresponding hydrocarbon derivatives, and this has allowed the study, for instance, of many long-lived valence-bond isomers

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of aromatic and heterocyclic systems [32] (see Chapter 9). This stabilising influence, denoted the ‘perfluoroalkyl effect’ [33], is considered to be kinetic rather than thermodynamic in nature [34]. The introduction of electron-withdrawing perfluoroalkyl groups into unsaturated systems lowers frontier orbital energies [35], as deduced by theory [36] and photoelectron spectroscopy [37] for a series of fluorinated alkenes, and manifestations of this effect are seen in much of the chemistry of such systems.

V STRENGTHS OF UNSATURATED FLUORO-ACIDS AND -BASES Since fluoroalkyl groups are uniformly acid-strengthening and the order of magnitude of the effect, relative to other haloalkyl groups, is consistent with electronegativities F > Cl, etc., it may be expected that the same situation occurs when fluorine is attached to unsaturated carbon. Inspection of the data in Table 4.5 quickly indicates a more complicated situation because, while fluorine substitution increases the acidity relative to the hydrocarbon analogue, the acidities are lower than the corresponding chlorocarbon compounds in the cases of the acrylic acids and phenols. Table 4.5 Strengths of unsaturated carboxylic acids and phenols [1, 7] Compound

pKa

CH2 5CHCOOH CF2 5CFCOOH CCl2 5CClCOOH C6 H5 OH C6 F5 OH C6 Cl5 OH C6 H5 COOH C6 F5 COOH

4.25 1.8 1.21 10.0 5.5 5.26 4.21 1.75

The fluorine atoms in these locations are not only inductively electron-withdrawing but interactions of the p-electron lone pairs of fluorine with the electron-rich double bond or aromatic ring can lead to a net electron donation; this effect has been studied by photoelectron spectroscopy [38, 39] (Figure 4.10). This Ip effect is discussed more fully in relation to fluorocarbanions (Section VII). O

O

F4

F

F

Figure 4.10

½38, 39


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99

It has been concluded from pKa measurements and fluorine NMR data on pentafluorobiphenyl derivatives, for example C6 F5 C6 H4 CO2 H, C6 F5 C6 H4 F etc., that the pentafluorophenyl group inductively withdraws electrons more strongly than phenyl but much less strongly than trifluoromethyl, whilst pentafluorophenyl and pentachlorophenyl have a similar capacity for electron withdrawal [40].

VI

FLUOROCARBOCATIONS

In this section we will be mainly concerned with situations where fluorine atoms are bonded to carbon, which has some formal charge F2Cþ 2, either directly or by conjugation, but we will also make reference to the effect of a fluorine atom in the situation F2C2Cþ 2. As a guide we can consider boron compounds as a useful qualitative model for carbocations, because of the isoelectronic relationship of a carbocation to boron, and we note immediately that comparative chemistry of boron halides is most commonly discussed in terms of 2p–p overlap being more effective with fluorine than with the other halogens [41]. For the 2B2C2C2F situation, we note that fluoroalkyl derivatives of tricovalent boron are extremely unstable with respect to migration of fluorine from a- or b-carbon atoms to boron. Thus the fluorine atoms in these positions are enhancing the electrophilic nature of boron and we might reasonably predict the same situation for a carbocation. This is indeed the case and, at the outset, two major effects of fluorine towards positively charged carbon centres can be envisaged; fluorine directly bonded to a positively charged carbon atom is stabilising, via p–p interactions, whilst fluorine that is b- to a positively charged carbon atom is inductively strongly destabilising (Figure 4.11). F C

F

C

F

Stabilising

C

C

Destabilising

Figure 4.11

A

Effect of fluorine as a substituent in the ring on electrophilic aromatic substitution

The course of electrophilic aromatic substitution can be represented as shown in Figure 4.12; on the basis of inductive effects of the halogens alone, we would expect the order of reactivity to be X5H > Br > Cl > F. E

H

E

E +

X

Figure 4.12

X

X

H

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100

Chapter 4

Table 4.6 Relative rates of para-chlorination and bromination of halobenzenes and halodurenes [42] Substituent (X)

H

F

Cl

Br

Partial rate factor, fp , for para-chlorination of C6 H5 X

1

6.3

0.4

0.25

1a

4.62

0.145

0.062

Relative rates of bromination of X Me

Me

Me a

Me

After statistical correction.

Generally, however, the reverse is the case (F > Cl > Br) (Table 4.6) and, as fluorine can in some cases increase the reactivity of an aromatic system relative to hydrogen, these data give a clear indication of resonance interaction between fluorine and the charged transition state (Figure 4.13) which is reflected in the negative (i.e. electron-donating) sþ p value (Table 4.7). E

H

E

H

+ F+

F

Figure 4.13

Whether fluorine can activate or deactivate an aromatic ring relative to hydrogen depends on the nature of the attacking electrophile. When the reagent is less reactive (late transition state) such as in molecular chlorinations and brominations [42, 43] (Table 4.6), resonance stabilisation of the Wheland-like transition state becomes far more important and so fluorine activates the system. On the other hand, nitration of fluorobenzene is slower than the corresponding reaction with benzene. Some s values [44] for the halogens are listed in Table 4.7 and the following general principles may be drawn from the data [43]. The sm and sþ m values indicate that fluorine influences the reaction centre mainly by the I effect, but as the values follow the inverse order of electronegativity it can be concluded that the þM effect may also be in operation

Table 4.7 s Values for halogen substituents on an aromatic ring [43, 44]

F Cl Br

so

sm

sþ m

sp

sþ p

0.93 1.28 1.35

0.335 0.375 0.39

0.35 0.40 0.405

0.06 0.225 0.23

0:075 0.115 0.15

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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres

101

at the meta position. Ortho halogens also activate in the order F > Cl > Br although the so values are potentially influenced by steric effects

B

Electrophilic additions to fluoroalkenes [45]

The orientations and rates of addition of electrophiles to partially fluorinated alkenes follow the arguments developed in the preceding sections. For example, the rates of addition of trifluoroacetic acid to 2-halopropenes (Table 4.8) are in the order F > Cl > Br and provide evidence of the enhanced stabilisation of a carbon atom bearing a positive charge by 2p–2p interaction with fluorine [46] (Figure 4.14). H+ + H2C

CFCH3

H3C

+ C

CH3

H3C

F

C

CH3

½46


F + CF3COO−

CH3 H3C

C

OCOCF3

F

Figure 4.14 Table 4.8 First-order rate constants for reaction of trifluoroacetic acid with CH2 5CXCH3 at 258 C [46] X

105 kðs1 Þ

kX =kH

H F Cl Br

4.81 340 1.70 0.395

1 71 0.35 0.082

The orientation of electrophilic addition to trifluoropropene was originally thought to be a reflection of the relative stabilities of the intermediate carbocations 4.15A and 4.15B (Figure 4.15), but it was subsequently found that trifluoropropene is dimerised, rather than protonated in highly acidic media [47, 48]. Deuterium labelling studies indicated that the reaction proceeds via initial fluoride ion abstraction to yield an intermediate allyl cation [49] (Figure 4.16). + CF3CHCH3 4.15A

Figure 4.15

+ CF3CH2CH2 4.15B

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102

Chapter 4 H FSO3H

F3C
CHCH2

F

H F

CF3CH=CH2 H

−

FSO3 HF

H

−

½49


(H shift)

CF3

−

F3C

FSO3 HF

F CH3 F

+

+

H CF3

H

H

CH3

Figure 4.16

A similar mechanism has been advanced for the dimerisation of hexafluoropropene [50] (Figure 4.17) and other fluorinated propenes [45, 51] to analogous dimers. SbF5

CF3CFCF2

F3C

F

½50
F

CF(CF3)2

Figure 4.17

C Relatively stable fluorinated carbocations The now-classic technique pioneered by Nobel Laureate George Olah and co-workers [52, 53] for preparing relatively stable long-lived carbocations, and their direct observation in solution by NMR, has been applied to the study of a number of classes of fluorinated carbocationic species [52–55], including alkyl, aryl, allyl and tropylium cations (Table 4.9). In general, a halogenated precursor is dissolved in either neat SbF5 or an SbF5 =SO2 mixture, at or below room temperature [56] (Figure 4.18). F i H3C

C F

CH3

H3C i, SbF5, −60  C, SO2

C

CH3

SbF6

½56


F

Figure 4.18

The 19 F NMR spectrum of the dimethylfluorocarbocation [56] shows that the fluorine is de-shielded by a massive 260 ppm from the covalent starting material and this observation argues quite commandingly for p( p–p) resonance stabilisation of the carbocation by fluorine (Figure 4.19). F

Figure 4.19

F

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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres

103

Table 4.9 Stable fluorinated carbocations observed in solution by NMR spectroscopy Carbocation

Ref.

CH3 CF2

[61]

Carbocation F

Ref.

F

[62]

F

F F

H3C

C

CH3

F

[56]

F

F

Ar

[50] F

F

CF2

[57]

(CF3)2CFCH2CF CH CFCH2CF3

[63]

F

[64]

C

[59]

CH3

F7

F

Ph

[57]

C Ar

F

F

Ph

ðC6 F5 Þ3 Cþ

[65]

2+

Ar

[66]

[67] C6F5

The difluorobenzyl cation (Figure 4.20) is stable under conditions in which the benzyl cation undergoes rapid polymerisation [57] and 13 C and 19 F NMR studies [58] have shown that, as the electron demand of the aromatic ring increases (i.e. R is electron-withdrawing), the p( p–p) donation of fluorine to the carbocation centre also increases, leaving the electron density at Cþ relatively constant for a variety of aromatic substituents. F CF2Cl

i, SbF5, −75 C, SO2

C

F

½57
R

R

Figure 4.20

CF2

i

R

SbF5Cl

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104

Chapter 4

Other Lewis acids, such as BF3 Et2 O, have been used to induce ionisation [59, 60] whilst protonation of suitably fluorinated unsaturated substrates may also lead to carbocationic species (Figure 4.21). F

F BF3.Et2O

F

½59


CH3CN

F7

F

F FSO3H, SbF5

½60


−78
C H

H

Figure 4.21

The protonation of fluorobenzene outlined above suggests that fluorine para to the methylene group stabilises the arenium ion more effectively than if fluorine is at the ortho position, whilst at positions meta to the methylene group fluorine is probably destabilising relative to hydrogen. Consequently, the trifluorobenzenium ion 4.22A is particularly stable whilst the corresponding tetrafluorobenzenium ion 4.22B is of reduced stability [52] (Figure 4.22). H

H

H

F

H

F

F

F

½52
4.22A F

F

4.22B

F

Figure 4.22

Of the several fluorine-containing dications that have been reported, the contiguous diallylic dication shown in Figure 4.23 (4.23A), as determined by NMR experiments, is unique. Furthermore, it seems to be the case that if fluorine atoms are sited at the centres of highest charge density, then very long conjugated systems are possible [68] (4.23B)

1 Fluoromethyl cations Gas-phase hydride affinity measurements suggest that the order of stability for the þ þ þ fluoromethyl cations is CHþ 3 < CF3 < CH2 F < CHF2 , indicating that the introduction of fluorine increases the stability of the cations relative to hydrogen [54]. The trifluoromethyl cation CFþ 3 has been generated and observed by IR spectroscopy upon photolysis of CF3 I in an argon matrix at very low temperatures [69]. However, attempts to observe CFþ 3 in solution by ionisation of trifluorohalomethanes [32] only resulted in the

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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres H

F

105

F

(CF3)2CFCH2 CH2CF(CF3)2 F

F

½68


H

4.23A H (CF3)2CFCH2

CH2CF3 F

F

n

n = 1−3

4.23B

Figure 4.23

production of CF4 , even though CFþ 3 is observed as a fragment ion in the mass spectra of many organofluorine compounds.

D

Effect of fluorine atoms not directly conjugated with the carbocation centre

Even though fluoroalkyl substituents are inductively electron-withdrawing, several cationic species have been studied in which a trifluoromethyl group is attached directly to the positively charged carbon centre [55]. The destabilising influence of a trifluoromethyl group is manifested in a comparison of the reaction rates for the solvolysis [70], via SN 1 processes, of the tosylates 4.24A and 4.24B in which the replacement of hydrogen by CF3 leads to a rate retardation of ca. 103 (Figure 4.24). Surprisingly, the introduction of a second trifluoromethyl, as in 4.24C, leads to only a slight reduction in the rate of solvolysis and this has been attributed to the fact that the positive charge in intermediate 4.24B is largely delocalised into the aromatic ring and so the introduction of a second electron-withdrawing substituent, as in 4.24C, has little effect on the stability of the resulting carbocation. When such delocalisation is not possible, however, the effect of attaching CF3 groups adjacent to the carbocation site on the rate of solvolysis is additive; for instance, compare the rates of solvolysis [71] for 4.25A, 4.25B and 4.25C in Figure 4.25. Resonance-stabilised long-lived carbocations such as 4.26A and 4.26B have been generated from precursor alcohols in superacidic solution [72] but, if conjugative stabilisation is absent as in 4.26C, then only protonated alcohols are observed. Similarly, ketones with up to three a-fluorine atoms can be protonated giving, for example, 4.26D, whilst hexafluoroacetone is not protonated in a superacidic medium [73] (Figure 4.26). Direct observation of a number of bridged halonium ions (X ¼ Br, Cl, I) is possible [74] when, for example, 2,3-dihalo-2,3-dimethylbutanes are ionised in SbF5 =SO2 mixtures; however, as yet, no analogous fluoronium ions have been observed in solution (Figure 4.27). Indeed, 13 C NMR studies suggest that ionisation of 2,3-difluoro-2,3-dimethylbutane gives a rapidly equilibrating mixture in which methyl 1,2-shifts, rather than fluorine shifts, occur [75] (Figure 4.28).

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106

Chapter 4 OTos H

OTos

H

H

OTos

CF3

F3C

CF3

½70


OMe

OMe

4.24A Relative rates of Solvolysis

4000 H

OMe

4.24B

4.24C

5.2 - 2.4

1

H

CF3

CF3

OMe

OMe 4.24B

Figure 4.24

AnO2SO

F3CH2CO R1 CF3CH2OH

R1

R1

R2

½71


R2

R2 Relative Rate

4.25A

R1 = R2 = H

1012

4.25B

R1 = CF3, R2 = H

106

4.25C

R1 = R2 = CF3

1

Figure 4.25

CF3

CF3

C

C

H

CH3

Figure 4.26

H O

½73


C F3C

4.26A

H O

4.26B

H

CH3

4.26C

F3C

CH3 4.26D

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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres H3C

CH3

H3C

X

Y

H3C

i

CH3

½74


CH3

H3C

X = Cl, Y = F, Cl X = Br, Y = F, Br X = I, Y = F

107

CH3

X

i, SbF5, SO2, −60
C

Figure 4.27 H3C H3C F

CH3 CH3

i

CH3 CH3

H3C H3C

F

H3C H3C

CH3 F

H3C

F

½75


i, SbF5, SO2, −90
C

Figure 4.28

However, mass-spectral breakdown patterns of PhOCH2 CH2 F suggest that a cyclic fluoronium ion can be observed as an ion-neutral complex in the gas phase [76], whilst calculations indicate that the fluoronium ion is more stable than the isomeric þ CH2 CH2 F ion [54]. Participation by fluorine remote from the reaction centre has been postulated to account for the product obtained from the reaction between 5-fluoro-1-pentyne and trifluoroacetic acid [46] (Figure 4.29). CF3COO

H F

F

OCOCF3 F

½46


CF3COOH F3COCO OCOCF3 H3C

F

Figure 4.29

Of course a bridged system must be involved, at least in the transition state, between boron and carbon in the decomposition of diazonium salts (Figure 4.30) and, indeed, transfer from trifluoromethyl has been observed [77] (Figure 4.30).

VII

FLUOROCARBANIONS

The term ‘carbanion’ is used in the present context as a general description of systems with negative charge on carbon, although this may be only fractional. It should also be remembered that the nature of the species will be dependent on the counter-ion and on the solvent [78]. Much of our information concerning substituent effects on fluorocarbanions comes from studies of the rates of base-catalysed hydrogen, deuterium and tritium

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108

Chapter 4

−

Ar-N2

BF4

N2

CF3

δ

−N2

δ

Ar----F----BF3

ArF

+ BF3

½77


CF3 40
C

F

COOEt

F

F

CF2

CF2

Et2O HCO3

Figure 4.30

exchange reactions and, consequently, the substituent effects refer strictly to the transition state 4.31B (Figure 4.31), although the effects are usually considered to apply also to the intermediate carbanion 4.31C. C

H

4.31A

δ− δ+ C H Base

C

4.31B

4.31C

+ H-Base

Product 4.31D

Figure 4.31

If a substituent lowers the activation energy for production of 4.31B, then we assume that the energy of 4.31C is also lowered. However, it must be remembered that 4.31C may still have a very short lifetime, i.e. it is kinetically unstable with respect to initial state 4.31A or some product 4.31D, even though we may refer to the effect of a substituent as being strongly stabilising. The effect of ‘internal return’, i.e. return from 4.31B to 4.31A, or from 4.31C to 4.31B, is also a complicating factor which affects the interpretation of kinetic acidities. Sometimes equilibrium data are available and, obviously, this reflects substituent effects on the energy of 4.31A and 4.31C directly.

A Fluorine atoms attached to the carbanion centre Superficially, we would expect the high electronegativity of fluorine to stabilise a carbanion centre, but measurements of acid strengths and exchange rates for a variety

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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres

109

Table 4.10 Base-catalysed deuterium exchange in haloforms [80] Haloform

Rate of exchangea (105 k) (l:mol1 s1 )

CHF3 CHCl3 CHBr3 CHI3 CHCl2 F CHBr2 F CHI2 F

Too slow to measure in this medium 820 101 000 105 000 16 3600 8800

a

08 C in water.

of halogenated compounds, discussed below, suggest that the inductive effect (Is ) of fluorine is not the dominant factor in determining the stability of the carbanions formed [79]. Base-catalysed H/D exchange experiments for a series of haloforms [80] (Table 4.10) demonstrate that carbanion formation is stabilised by halogen in the order I > Br > Cl > F. When these results are combined with acidity measurements which show that CF3 H ðpKa 31Þ is little more acidic than methane (pKa 40) [81], we can conclude that, in these systems, fluorine attached to a carbanion centre is stabilising with respect to hydrogen but destabilising compared with the effects of other halogens. Similar conclusions can be drawn from pKa measurements of a number of halobis(trifluoromethyl) methanes [82]. On the other hand, the pKa values of a series of substituted nitromethanes [83] (Table 4.11) suggest that, whilst chlorine bonded directly to the carbanion centre increases acidity relative to hydrogen, fluorine decreases acidity and, therefore, decreases the stability of the corresponding carbanion. To rationalise these two contradictory results we must consider not only the stabilising inductive effect of fluorine (Is ), but also destabilising interactions between the electron pairs on fluorine and the non-bonding electron pair at the negatively charged carbon atom (Ip ) which, for the halogens, follows the order F > Cl > Br > I [84] (Figure 4.32). Iσ H2C

F

Stabilising

−Iπ

H2C

F

Destabilising

Figure 4.32

Table 4.11 Apparent ionisation constants of substituted nitromethanes (in water, at 258 C) [83] XYCHNO2 Y ¼ COOC2 H5 X ¼ Cl X¼H X¼F Y ¼ Cl X ¼ Cl X¼H X¼F

pKa

XYCHNO2

pKa

4.16 5.75 6.28

Y ¼ NO2 X ¼ Cl X¼H X¼F

3.80 3.57 7.70

5.99 7.20 10.14

½84


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110

Chapter 4

The net stabilising or destabilising influence of fluorine attached to a carbanion centre is, therefore, a result of these two effects. A consideration of the geometry of carbanions formed at both planar and tetrahedral carbon, as depicted in Figure 4.33, illustrates that Ip repulsion is greater at a planar carbon since, in this situation, the repelling nonbonding electron pairs on carbon are closer in space to electron pairs on fluorine [79] (Figure 4.33). 90 

109 

C

109 

F

Tetrahedral (sp3) C

½79
C

F

109 

Planar (sp2) C

Figure 4.33

Consequently, for the haloform case (Table 4.10), since Ip repulsion for chlorine is less than that for fluorine, chlorine as a substituent facilitates carbanion formation much more than fluorine. The enhanced acidities of bromoform and iodoform have been attributed to the release of steric strain on deprotonation, while the increased availability of d-orbitals and the easier polarisation of these larger atoms [85] are effects that are at a minimum for fluorine (Figure 4.34). C

Br

C

Br

½85


Figure 4.34

The carbanion centres in nitro derivatives described in Table 4.11 are more planar in character due to conjugative stabilisation of the negative charge by the nitro group, and the fact that here fluorine destabilises the carbanions relative to hydrogen as a consequence of Ip repulsion dominating over Is stabilisation. Also, the nature of other groups attached to the central carbon affects the level of conjugation of the negative charge with the nitro group and, consequently, the stereochemistry of the carbanion site. A propensity of fluorocarbanions to adopt pyramidal structures in which Ip repulsions are minimised is supported by calculations [86] from which it was deduced that for the  CH2 F carbanion a pyramidal structure is 55 kJmol1 more stable than the planar form. Furthermore, calculations concerning a-fluorocyclopropyl anions [87] suggest that a non-planar conformation is adopted and that the barrier to inversion is significantly higher for a monofluorinated ring (175 kJmol1 ) than for the cyclopropyl anion (73 kJmol1 ).

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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres

B

111

Fluorine atoms and fluoroalkyl substituents adjacent to the carbanion centre

When a fluorine atom is located b- to a carbanion centre, F2C2C , we would expect the high electronegativity of fluorine to give rise to a very dominant stabilising effect (Is ), since, in this situation, there is no opportunity for Ip repulsion. Indeed, b-fluorine substituents are very strongly stabilising but the basis of the effect has been a subject of varied interpretation. Attempts to determine the effect on carbanion formation of halogen atoms attached to the adjacent carbon are generally complicated by a competing b-elimination process [88] (Figure 4.35). However, Andreades [89] found that, for a series of monohydrofluorocarbons, the exchange process proceeds much more rapidly than elimination; the forward (kH ) and reverse (kD ) reactions were studied (Figure 4.36; Table 4.12). These observed relative reactivities and derived acidities indicate that the stabilities of perfluorocarbanions are in the order tertiary > secondary > primary and, therefore, that b-fluorine (F2C2C ) is much more effective at carbanion stabilisation than a-fluorine (F2C ) [79]. A further demonstration of these effects is observed for ðCF3 Þ3 CH, which is 50 orders of magnitude more acidic than methane. Furthermore, pentafluorocyclopentadiene [90] is only slightly more acidic than cyclopentadiene (pKa 15) whereas pentakis(trifluoromethyl)cyclopentadiene ðpKa < 2Þ is even more acidic than conc. nitric acid [32, 32a]! D

C

C

D2O

Hal

C

C

Hal

−Hal

C

½88


C

Figure 4.35

RFH

+

CH3OD

kH

RFD

+

CH3OH

½89


kD (NaOCH3)

Figure 4.36

The enhanced stability of b-fluoro carbanions (Figure 4.37) has been attributed to fluorine negative hyperconjugation (FNHC; see Section IIIB). For instance, negative hyperconjugation (see Section III) has been invoked to explain the enhanced reactivity (100-fold) [27] and the higher gas-phase acidity (by 5.4 pKa units) [91] of 4.38A over the Table 4.12

Deuterium exchange and acidities of monohydroperfluoroalkanes [89] CF3 ðCF2 Þ5 CF2 H

ðCF3 Þ2 CFH

ðCF3 Þ3 CH

CF3

CF3 ðCF2 Þ5 CF 2

ðCF3 Þ2 CF

ðCF3 Þ3 C

Relative reactivity

1

6

2  105

109

Approx. pKa

31

30

20

11

Compound

CF3 H

Derived ion



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112

Chapter 4

C

C

F

F F F

C

F

C F

Figure 4.37

bridgehead compound 4.38B in which negative hyperconjugation in the derived carbanion is unfavourable. Elongated b-C2F bonds and shortened Ca 2Cb bonds in 4.38C, as measured by X-ray crystallography, provides direct experimental evidence [23] (Figure 4.38). CF3 (CF3)3C

H

(Me2N)3S+

CF3

H 4.38A

F

F

½27


4.38B

4.38C

Figure 4.38

The stereochemical course of hydrogen–deuterium exchange in homochiral PhEtHC CF3 has been studied [15] and, like systems containing other carbanionstabilising groups, the extent of racemisation of the product varies with solvent.

C Stable perfluorinated carbanions [92–94] Inevitably, the successful generation of long-lived carbocations by the protonation of alkenes in superacid solution prompted attempts to generate observable perfluorocarbanions by the reaction of fluoride ion with perfluoroalkenes (‘Mirror-image chemistry’). Although fluoroalkenes can oligomerise in the presence of fluoride ion, there are now reported examples [79, 95] of fluorocarbanions that can be observed directly by NMR and, in some cases, obtained as crystalline solids [96]. Their generation is achieved by reaction of either a fluoroalkene [97] or an allene [98] with a fluoride-ion source, usually CsF or TAS-F [99], in a suitable solvent at room temperature. Various tertiary perfluorocarbanions have been directly observed but carbanions with a-fluoro substituents are usually too unstable, due to Ip repulsion (Figure 4.39). The anion 4.39A shown in Figure 4.39 is an exception [100]. Fluoride-ion-promoted carbon–carbon bond cleavage enabled the preparation of the cyclic carbanion shown in Figure 4.40 [23]. Sigma-complexes, observed by NMR, are analagous to the well-known Wheland intermediates in hydrocarbon chemistry, is possible upon the addition of CsF to perfluoro-striazine derivatives [101] (Figure 4.41) but direct observation of similar s-complexes derived from less-activated perfluoroaromatic systems has not yet been reported. Deprotonation of hydroperfluorocarbons provides an alternative route to perfluorocarbanions and, for example, several perfluoropentadienide [90, 102–104] (Figure 4.42) and benzylic [105] carbanions have been prepared by this method. A cyclopentadienide ion can also be prepared by reaction of a diene with Bu4 NI via a single-electron transfer pathway [104] (Figure 4.43).

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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres F3C

F3C

i C

CF2

C

F3C

½97


Cs+

CF3

113

F3C i, CsF, tetraglyme F

i F

+

F

F

F

F

F

Cs+

½95


i, CsF, tetraglyme

F CF3

F3C F3C

F3C

i

•

CF3

CF3

CF3

(Me2N)3S+

½98


CF3

i, (Me2N)3S+Me3SiF2− (TAS-F), THF F

F

Cs+

F

½100


4.39A

Figure 4.39 F

F

CF3 THF

F

CF3

F

TAS-F

F3C

½23


F

F F3C

F

F

(Me2N)3S+

Figure 4.40 F N

N

F

N

N

F N

Cs+ F

N

½101


F

Figure 4.41

D

Acidities of fluorobenzenes and derivatives

Inductive effects of ortho substituents are important in governing the acidity of a C–H bond in substituted benzenes [106], and a variety of data indicate that the acidifying influence of fluorine falls off in the order ortho  meta > para; this is illustrated by Table 4.13 [107].

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114

Chapter 4

CF3 CF3

CF3

H CF3

CF3

CF3

H2O CF3

½103, 104


H3O

CF3

CF3

CF3

Figure 4.42

CF3 CF3

CF3

CF3 CF3

CF3

CF3

Bu4NI CF3

CF3

Bu4N CF3

CF3I

½104


CF3

Figure 4.43 Table 4.13

Relative rates of base-catalysed deuterium exchange [107] Rate, relative to

Compound

Benzene 6:3  10 107 11.2 580 —

[2-D] Fluorobenzene [3-D] Fluorobenzene [4-D] Fluorobenzene [3-D] Benzotrifluoridea 2,5-Difluoro[Me-D1 ]toluene a

Toluene

5

— — — — 350

Trifluoromethyl [3-D] benzene.

Also, the order of acidity of the dihalobenzenes, m-C6 H4 F2 > m-C6 H4 ClF > m-C6 H4 Cl2 , obtained from exchange data on the monodeutero derivatives [88], indicates the greater acidifying influence of ortho-fluorine than of ortho-chlorine and is a further illustration of the significance of inductive effects. Polyfluorobenzenes are very acidic, as evidenced by the fact that pentafluorobenzene and 1,2,4,5-tetrafluorobenzene, for example, are metallated with butyl lithium rather than undergoing nucleophilic substitution [108]; see Chapter 9, Section IIE. This is illustrated by the data in Table 4.14, which contains a comparison of rates of exchange of tritium and of nucleophilic substitution. Table 4.14 Rates of tritium exchange and of nucleophilic substitution by sodium methoxide [109] 104 k ðl:mol1 s1 Þ Polyfluorobenzene Pentafluorobenzene 1,2,3,4-Tetrafluorobenzene 1,2,4,5-Tetrafluorobenzene 1,2,3,5-Tetrafluorobenzene 1,3-Difluorobenzene

Exchange at 408 C 1360 0.0053 58 5.6 0.0061

Displacement at 508 C 1.05 0.018 < 104 0.049

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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres

115

Also relating to these data is the observation that substitution accompanies metallation in the reaction of 1,2,3,4-tetrafluorobenzene with butyl lithium [108]. Fluorine substituents in the ring also enhance the acidity of hydrogen at benzylic positions [82]; for example, the acidity of 2,5-difluorotoluene relative to toluene is shown in Table 4.13. Indeed, a comparison of the equilibrium acidities of C6 F5 Þ2 CH2 and ðC6 F5 Þ3 CH with the values for diphenylmethane and triphenylmethane indicates that substitution of each phenyl group by pentafluorophenyl results in an enhancement of acidity by 5–6 pK units; this effect has also been attributed, principally, to a strong inductive influence by polyfluoroaryl groups [110].

E

Acidities of fluoroalkenes

Studies on the influence of halogen on the acidity of hydrogen in 1-chloro-2-fluoroethene showed that the kinetic acidity of the hydrogen a- to chlorine is greater than that for hydrogen a- to fluorine, in accordance with lower Ip repulsions for chlorine a- to the carbanion centre [79]. Similarly, the pKa values for a range of halogenated ethenes [26] (Table 4.15) demonstrate that a-halogen substituents facilitate vinyl carbanion formation in the same order as in the haloform series, i.e. Br > Cl > F. Calculations suggest that negative hyperconjugation is also a factor in vinylic systems although the vinyl anions are thermodynamically unstable relative to the formation of ethyne and fluoride ion [111]. Table 4.15 Acidities of halogenated alkenes [26]

VIII A

Carbon acid

pKa

CCl2 5CHBr CCl2 5CHCl CF2 5CHCl CCl2 5CHF CF2 5CHF

24.6 25.0 25.3 26.3 27.2

FLUORO RADICALS [112, 113] Fluorine atoms and fluoroalkyl groups attached to the radical centre

The organic chemist is interested in the separate effects of fluorine substituents on (a) the rate constants for formation of radicals and (b) the effect on the subsequent reactivity of these radicals; but it is not always easy to disentangle this information from experimental observations. Do fluorine substituents have an effect on thermodynamic stabilisation, or not? We might expect fluorine to have a similar stabilising influence to that of oxygen on the formation of radicals (Figure 4.44). However, we have already noted the schizophrenic nature of fluorine in carbanions, where inductive electron withdrawal wrestles with Ip electron repulsion, and it is a similar situation with radicals.

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 116

116

Chapter 4

O

O

CH2

CH2

Figure 4.44

Stabilities of methyl and fluoromethyl radicals have been calculated [114] to be in the order CF3 < CH3 < CF2 H < CFH2 and the relative rates of formation of such radicals, measured in b-scission reactions of a series of t-butoxy radical derivatives, as shown in Figure 4.45, lend support to this conclusion [115]. l

l

l

l

O + CH3 R

C

O

∆

CO2

CH3

k1

CH3 R

C

CH3

½115


O k2

CH3

2

R

CH3

O H3C

+

R

CH3

Figure 4.45

Methyl radicals are essentially planar but ESR measurements [116], supported by theoretical calculations [114], show that fluoromethyl radicals deviate from planarity to increasingly pyramidal structures upon further fluorination, with CF3 l measured to be 49.18 from planarity. The barriers to inversion of fluoromethyl radicals increase in the order CFH2 < CF2 H < CF3 while fluorocyclopropyl radicals (Figure 4.46) adopt a fixed pyramidal conformation at the radical centre [117], as determined by ESR at 1088 C. The tendency for fluorine to induce pyrimidalisation of radical centres has also been used to account for the stereochemistry of products [118]. l

l

l

F

½117
H3C

CH3

Figure 4.46

Electronegative groups lower orbital energies and therefore, in principle, the high electronegativity of fluorine should lower the orbital energy of an attached carbon radical centre. Additionally, conjugative interactions between the singly occupied orbital of the carbon and the lone pairs on fluorine would be a stabilising interaction, which would simultaneously render the carbon atom more nucleophilic (Figure 4.47). The fact that further stabilisation by fluorine substitution is negligible, after the first substituent, suggests that Ip repulsion becomes more important as we increase the charge on carbon and this also accounts for the tetrahedral nature of the trifluoromethyl radical. This is exactly analogous to the effect of fluorine substituents on carbanions, where electron-pair repulsions are minimised in a pyramidal conformation (Figure 4.48).

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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres

H

117

H C

F

H

C

F

C

F

H

Figure 4.47 H

H C

F

F

F

Figure 4.48

B

Stable perfluorinated radicals

The effect of fluorine substituents that are not directly attached to the radical centre is more difficult to define, although calculations [114, 119] suggest an order of stability CH3 CH2 > FCH2 CH2 > F2 CHCH > CH3 > CF3 CH2 which is, intuitively, the opposite of the order which might be anticipated. Obviously, polyfluoroalkyl substituents will be strongly electron-withdrawing, making the radical more electrophilic in character and in some cases steric crowding is so severe at multi-substituted radical centres that the radicals are kinetically very stable. An example is the ‘Scherer radical’ [120] (Figure 4.49), which is stable at room temperature, even in the presence of oxygen. l

l

F F3C

l

l

l

CF3 CF3

F2

F F3C

CF3 C2F5

F3C F

F

F3C F

CF3

½120


CF3

Figure 4.49

Likewise, the radical shown in Figure 4.50 is a stable perfluorovinyl system [121].

(CF3)3CFC CCF(CF3)3

CF(CF3)3

F2 C (CF3)3CF

C

½121
F

Figure 4.50

C

Polarity of radicals

It is increasingly apparent that polar characteristics of radicals are important in organic synthesis [122] and the effect of fluorine on the polarity of radicals is very significant. Reactions of perfluoroalkyl radicals with a series of substituted p-styrenes [123] (Figure 4.51) shows that the rate constant for radical addition to alkenes increases as the alkene becomes more electron-rich (Table 4.16) and, in similar additions, perfluoroalkyl radicals reacted 40 000 times faster with 1-hexene than the corresponding alkyl radicals.

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 118

118

Chapter 4 C8F17 +

½123


C8F17

R

R

Figure 4.51 Table 4.16 Relative rates of addition of perfluoro-octyl radicals to para-substituted styrenes [123] R

rel kadd

OCH3 CH3 H Cl CF3

1.41 1.33 1.0 0.77 0.53

Likewise, perfluorinated radicals react more rapidly with electron-rich alkenes (X¼H) than with electrophilic alkenes (X¼F) in some intramolecular processes [124] (Figure 4.52). Similarly, rates of hydrogen abstraction by perfluoroalkyl radicals from a series of aromatic thiols were greatest from the most nucleophilic thiol [125]; clearly, taken together, these data show that perfluoroalkyl radicals are highly electrophilic in character, in comparison with alkyl radicals, which are of course more nucleophilic. X X

X

X F2C

CF2

X

CX2H

CF2

+ F

X

H F

X

CF2

½124
4.52A

4.52B

X = F, kA 4.9 x 105 s−1, Only 3-4% 4.52A formed X = H, kA 1.06 x 107 s−1, kB 3.5 x 106 s−1

Figure 4.52

REFERENCES 1 B.E. Smart in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 57. 2 C.W. Thornber, Chem. Soc. Rev., 1979, 8, 563. 3 S.A. Sherrod, R.L.d. Costa, R.A. Barnes and V. Boekelheide, J. Am. Chem. Soc., 1974, 96, 1565. 4 R. Gallo, Prog. Phys. Org. Chem., 1983, 14, 115. 5 D. Seebach, Angew. Chem., Int. Ed. Engl., 1990, 29, 1320. 6 M. Schlosser, Angew. Chem., Int. Ed. Engl., 1998, 110, 1497. 7 R. Stewart, The Proton: Applications to Organic Chemistry, Academic Press, London, 1985. 8 G.V. Calder and T.J. Barton, J. Chem. Educ., 1971, 48, 338.

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R.D. Chambers and J.F.S. Vaughan in Organofluorine Chemistry. Fluorinated Alkenes and Reactive Intermediates, ed. R.D. Chambers, Springer Verlag, Berlin, 1997, p. 1. R.D. Chambers, R.S. Matthews, G. Taylor and R.L. Powell, J. Chem. Soc., Perkin 1, 1980, 435. W.B. Farnham, D.A. Dixon and J.C. Calabrese, J. Am. Chem. Soc., 1988, 110, 2607. A.E. Bayliff and R.D. Chambers, J. Chem. Soc., Perkin 1, 1988, 201. W.B. Farnham, W.J. Middleton, W.C. Fultz and B. E. Smart, J. Am. Chem. Soc., 1986, 108, 3125. B.E. Smart, W.J. Middleton and W.B. Farnham, J. Am. Chem. Soc., 1986, 108, 4905. R.D. Chambers and T. Nakamura, J. Chem. Soc., Perkin Trans. 1, 2001, 398. R.D. Chambers, P.D. Philpot and P.L. Russell, J. Chem. Soc., Perkin 1, 1977, 1605. R.D. Chambers and M.P. Greenhall, J. Chem. Soc., Chem. Commun., 1990, 1128. E.D. Laganis and D.M. Lemal, J. Am. Chem. Soc., 1980, 102, 6633. R.D. Chambers, S.J. Mullins, A.J. Roche and J.F.S. Vaughan, J. Chem. Soc., Chem. Commun., 1995, 841. R.D. Chambers, M.P. Greenhall and M.J. Seabury, J. Chem. Soc., Perkin 1, 1991, 2061. A. Streitwieser and J.H. Hammons, Prog. Phys. Org. Chem., 1965, 3, 41. A. Streitwieser and F. Mares, J. Am. Chem. Soc., 1968, 90, 644. R.J. Harper, E.J. Soloski and C. Tamborski, J. Org. Chem., 1964, 29, 2385. A. Streitwieser, J.A. Hudson and F. Mares, J. Am. Chem. Soc., 1968, 90, 648. R. Filler and C.-S. Wang, J. Chem. Soc., Chem. Commun., 1968, 287. P.v.R. Schleyer and A.J. Kos, Tetrahedron, 1983, 39, 1141. W.R. Dolbier, Chem. Rev., 1996, 96, 1557. W.R. Dolbier in Organofluorine Chemistry. Fluorinated Alkenes and Reactive Intermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 97. D.J. Pasto, R. Krasnansky and C. Zercher, J. Org. Chem., 1987, 52, 3062. X.K. Xiang, X.Y. Li and K.Y. Wang, J. Org. Chem., 1989, 54, 5648. R.W. Fessenden and R.H. Schuler, J. Chem. Phys., 1965, 43, 2704. T. Kawamura, M. Tsumara, Y. Yokomichi and T. Yonezawa, J. Am. Chem. Soc., 1977, 99, 8251. S.F. Wnuk, D.R. Companioni, V. Neschadimenko and M.J. Robins, J. Org. Chem., 2002, 67, 8794. A. Pross and L. Radom, Tetrahedron, 1980, 36, 1999. K.V. Scherer, T. Ono, K. Yamanouchi, R. Fernandez, P. Henderson and H. Goldwhite, J. Am. Chem. Soc., 1985, 107, 718. B.L. Turmanskii, V.F. Chestkov, N.I. Delyagina, S.R. Sterlin, N.N. Bubnov and L.S. German, Russ. Chem. Bull., 1995, 44, 962. W.B. Motherwell and D. Crich, Free Radical Chain Reactions in Organic Synthesis, Academic Press, London, 1992. D.V. Avila, K.U. Ingold, J. Lusztyk, W.R. Dolbier, H.Q. Pan and M. Muir, J. Am. Chem. Soc., 1994, 116, 99. X.X. Rong, H.Q. Pan and W.R. Dolbier, J. Am. Chem. Soc., 1994, 116, 4521. W.R. Dolbier and X.X. Rong, Tetrahedron Lett., 1994, 35, 6225.

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Chapter 5

Nucleophilic Displacement of Halogen from Fluorocarbon Systems

It is the aim of this chapter to develop a model for the very broad spectrum of reactivity of fluorine-containing systems towards nucleophiles. Substituent effects of fluorine and fluorocarbon groups on the SN 1 process were considered earlier, in a more general discussion of carbocations (see Chapter 4, Section VI); effects on the SN 2 process will now be examined. Then the broader principles of displacement of fluorine, as fluoride ion, from carbon in different environments will be discussed to emphasise why, for example, nucleophilic displacement of fluoride ion from perfluoroalkenes occurs extremely rapidly while, in contrast, perfluoroalkanes are characterised by extreme inertness.

I SUBSTITUENT EFFECTS OF FLUORINE OR FLUOROCARBON GROUPS ON THE SN2 PROCESS In general, substituent effects on the SN 2 process are not easy to predict [1] because, in principle, electron-withdrawing or -donating groups can either accelerate or retard the process, depending on whether bond making, between carbon and nucleophile, or bond breaking, between carbon and the leaving group, is emphasised. The situation is further complicated by substituent effects either resulting in mechanistic change or creating very significant steric effects. Nevertheless, halogen substituents not directly attached to the reaction centre usually reduce SN 2 reactivity in alkyl halides [2], as illustrated by the data in Table 5.1. Clearly, the effects are not large and are not very different for the individual halogens. Similarly, nucleophilic displacements from centres substituted with CF3 groups are retarded [3–5] in comparison with corresponding alkyl derivatives, due to steric hindrance and fluorine lone-pair repulsion of the incoming nucleophile, but preparatively useful Table 5.1 Reactivities of RBr towards NaOPh (in MeOH at 208 C) [2] R

k (l:mol
1 s
1  104 )

CH3 CH2 CH3 CH2 CH2 FCH2 CH2 ClCH2 CH2 BrCH2 CH2

122

Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

39.1 25.6 4.95 5.61 4.99

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Nucleophilic Displacement of Halogen from Fluorocarbon Systems

123

reactions are possible when a sufficiently good leaving group, such as tosyl, is employed [6] (Figure 5.1). The effect of introducing fluorine a-, b- or g- to the reaction centre in solvolysis reactions can be very substantial, especially inhibiting SN 1 processes [7, 8]. CF3CH2X

+

I−

CF3CH2I

+

X−

½6

Figure 5.1

A single-electron transfer process may be a competing mechanism in reactions between sterically demanding nucleophiles and CF3 CH2 I, since side products arising from radical coupling reactions are observed [9]. In contrast, fluorine or fluorocarbon groups directly attached to the reaction centre have a much more pronounced effect [4]; for example, the hydrolytic displacement of chloride from PhCHFCl appears to be activated with respect to benzyl chloride [10], although the situation is complicated by concomitant SN 1 and SN 2 processes. Nucleophilic substitution of halogen in RF CF2 Hal systems is very difficult, due to a combination of steric effects and shielding of the carbon skeleton by surrounding non-bonding pairs on fluorine, and there are no examples of halogen substitution by an SN 2 process involving these substrates. For example, RCF2 Br compounds are quite inert to halide exchange under conditions where CH3 CH2 Br is reactive [4]. However, in principle there are other ways in which RF Hal systems could react with nucleophiles, namely: (1)

Nucleophilic attack on halogen (Figure 5.2). However, this process is often very difficult to distinguish from the single-electron process, (2), shown below. Burton and co-workers have demonstrated that phosphorous nucleophiles react with CF2 Br2 to give synthetically useful ylids and they suggested carbene intermediates to explain their findings [11] (Figure 5.3). Halophilic attack on polyfluorinated systems, followed by b-elimination to give intermediate polyfluorinated alkenes that are susceptible to nucleophilic attack, has also been suggested [12] (Figure 5.4). Nuc

+ I
CF3

H

Nuc
I + CF3

Solvent

CF3H

Figure 5.2

R3P

+

CF2Br2

R3PBr

CF2

CF2Br

+

+

CF2Br

Br

½11 R3P

+

R3P
CF2

Figure 5.3

CF2

+

R3P-CF2

R3PBr

Br

(R3PCF2Br)

Br

R3P

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 124

124

Chapter 5

+

PhS

PhSBr

CF2CF2Br

Br

CF2CF2Br

+

½12 PhSCF2CF2Br

PhSBr

PhS

PhSCF2CF2

CF2CF2

Figure 5.4

(2)

Single-electron transfer (SET) [13, 14] (Figure 5.5). RF
I

Nuc

RF
I

Nuc

RF
I

RF

e.g.

I

RF i NR2

etc

RF I

+

NR2 NR2

½13, 14 I

−H+ RF

RF O

i , RFI (RF

= C8F17 ), Pentane,

H3O

+ HI

NR2 uv

Figure 5.5

(3)

A radical chain process (SRN 1) (Figure 5.6).

Nuc

RF

+

+ Nuc

RF-I

Nuc

Nuc-RF

+ RFI

RF-I

Nuc-RF

RF

+

+ I

RF-I

etc

Figure 5.6

An essential feature of this process is the reaction of a nucleophile with a fluorocarbon radical. It is important to emphasise that radicals, being electron-deficient, are electrophilic and therefore that fluorocarbon radicals are even more electrophilic. These processes are, of course, aided by ultraviolet irradiation and inhibited by radical traps, or the radicals may be intercepted, e.g. by norbornene as in the example shown in Figure 5.7a [15]. Further examples are given in Table 5.2.

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 125

Nucleophilic Displacement of Halogen from Fluorocarbon Systems

125

(CF3)2CFSPh PhS (CF3)2CF

(CF3)2CFI

Norbornene

½15 CF(CF3)2 (CF3)2CFI

I

(CF3)2CF

CF(CF3)2

Figure 5.7a Table 5.2 Substitution of halogen in RCF2 Hal systems Substrate

Nucleophile, conditions

Product

Yield (%)

Ref.

53

[16]

50

[17]

94

[18]

CH3

C5 F11 CF2 I




NO2 ðCH3 Þ2 C Li DMF, 3 h

O

C6F13

NO2

C CH3 H

O OEt

−

ClCF2 CF2 I

þ

CO2Et

+

Na

ClCF2 CO2Et O2N

O2N

N

N +

Bu4N

C5 F11 CF2 I N −

Electrochemistry, CH3 CN

C6F13

N H

CF2 BrCF2 Br

PhO
Kþ HMPAa, rt

PhOCF2 CF2 Br

C6 F13 Br

PhS
Kþ DMF, rt

C6 F13 SPh

62

[20]

C6 F13 I

PhS
Bu4 Nþ Benzene, H2 O, rt

C6 F13 SPh

76

[15]

CF2 Br2

Ph3 P Diglyme, rt

ðPh3 PCF2 BrÞþ Br


100

[11]

a

HMPA, hexamethylphosphoric triamide.

[19]

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 126

126

Chapter 5

Formally, an aromatic system acts as the nucleophile in SET processes involving haloperfluoroalkanes, although the orientation pattern indicates an aromatic sustitution by a fluorocarbon radical [21, 22] (Figure 5.7b). OMe

H(CF2)4Cl

+

C6H5OCH3

i

(CF2)4H

½21, 22

i, Na2S2O4, NaHCO3, DMSO ortho : meta : para = 50 : 35 : 15

Figure 5.7b

The processes described above invoke breakdown of intermediate radical-anions to give perfluoroalkyl radicals and halide ion; this is supported by theory [23] and ESR studies [24]. However, t-perfluoroalkyl iodides do not react with nucleophiles in this manner because it is thermodynamically more favourable for these particular intermediate radical-anions to break down into relatively stable perfluorocarbanions and iodine atoms [23] (Figure 5.8). The reaction of tertiary perfluoroalkyl iodides and hexene to give perfluoroalkenes supports this conclusion [25]. C3F7C(CF3)2I

i

−I

[C3F7C(CF3)2I]

C3F7C(CF3)2

i, Zn, CH2CHR, AcOEt, 80 C

½23

−F

CF3CF2CFC(CF3)2

CF3CF2CF2C(CF3)CF2 5

1 90%

Figure 5.8

Remarkably, electron transfer from phenylthiolate anions to perfluorodecalin occurs, to give naphthalene derivatives [26]. It is not clear why this has not proved to be a general process but it may be considered to involve a series of electron transfer steps (Figure 5.9).

A Electrophilic perfluoroalkylation The 2CF2 I group may be activated towards nucleophilic attack by enhancing the leaving group ability of iodine through expansion of its valence shell to an iodonium species, and this has culminated in the development of a range of electrophilic perfluoroalkylphenyliodonium triflate (FITS) reagents [27] (Figure 5.10). These remarkable electrophilic reagents have been used to carry out perfluoroalkylation of various nucleophilic systems, including carbanions, activated aromatics and enolate derivatives; examples are shown in Figure 5.11.

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 127

Nucleophilic Displacement of Halogen from Fluorocarbon Systems

+1e

−F

F

F

F

F

F

F

127

½26

+1e +1e etc. F

F

F

F

−F

F

F

PhS SPh PhS

SPh

PhS

SPh

i

F

F

SPh

SPh

SPh

i, PhS Na, DMEU, 70 C, 10 days

Figure 5.9 i

RFI

RFI(OCOCF3)2

ii

O-Tf

RF I Ph

i,

½27

80% H2O2, (CF3CO)2O

ii, Benzene, CF3SO2OH (TfOH)

Figure 5.10

PhCH2MgCl

C3F7IPh

O
Tf

−110 C

PhCH2C3F7

82%

O

OTMS +

C8F17

I Ph

O
Tf

MeCN, 45 C

C8F17 76%

Figure 5.11

A range of related trifluoromethylating agents in which the perfluoroalkyl group is attached to a sulphonium leaving group have also been developed, as indicated in Figure 5.12.

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 128

128

Chapter 5

DMF, 80 C

+ O-Tf

N

S

H

CF3

N

CF3

H

90%

Figure 5.12

II FLUORIDE ION AS A LEAVING GROUP The wide range of reactivity of the carbon–fluorine bond, referred to at the beginning of this chapter, must obviously be attributable to variations in the mechanism of the substitution process and, in particular, to the amount of bond breaking in the transition state [28].

A Displacement of fluorine from saturated carbon – SN2 processes In addition to the two overall nucleophilic displacement processes, SN 1 and SN 2, we can envisage a spectrum of transition states for the SN 2 process. Various stages can be represented by 5.13A, in which there is little or no carbon–fluorine bond breaking; 5.13B, which is concerted; and 5.13C, where carbon–fluorine bond breaking is in advance of the new bond being formed (Figure 5.13). δ+ Nuc

δ− C 5.13A

F

δ+ Nuc

C 5.13B

δ− F

δ+ Nuc

C

δ− F

5.131C

Figure 5.13

Of course, the extreme of 5.13A would be complete bond formation with the nucleophile in an addition–elimination process, such as can occur when fluorine is bound to unsaturated carbon. Since a fluorine atom attached to carbon leads to a very polar, yet very strong, Cdþ
Fd
bond, we have two conflicting effects: (a) the attached carbon is electron-deficient and therefore susceptible to nucleophilic attack; (b) if the transition state involves much carbon–fluorine bond breaking, it may be of relatively high energy depending on the degree of solvation of the developing fluoride ion. Also, fluorine is not a polarisable atom and this contributes to the high energy of the process. Consequently, because carbon–chlorine bonds are weaker and more polarisable, the ratio kF =kCl , for displacement from the corresponding fluorides and chlorides, is regarded as a useful probe for indicating the amount of carbon–halogen bond breaking in the transition state. Factor (b) is the more important with alkyl fluorides since they are, for example, much less readily hydrolysed than other alkyl halides (Table 5.3), but it is also evident that the reactivity ratios are influenced considerably by the reagent. Fluoride ions (or incipient fluoride ions) form very strong hydrogen bonds, much stronger than corresponding bonds to chloride, and so a change to a more hydrogen-

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Nucleophilic Displacement of Halogen from Fluorocarbon Systems

129

Table 5.3 Relative reactivities of isoamyl halides ðCH3 Þ2 CHðCH2 Þ2 X with piperidine and sodium methoxide at 188 C [29] Reagent

X¼F

C5 H11 N CH3 ONa=CH3 OH

1 1

X ¼ Cl

X ¼ Br

X¼I

68.5 71

17 800 3500

50 500 4500

Table 5.4 Fluorine : chlorine rate ratios for reactions of alkyl halides [28] Halide

Reagent

Solvent

Temp. (8 C)

Ph3 CX Ph2 CHX PhCH2 X CH3 X

H2 O H2 O/EtOH H2 O H2 O

85% aq. Me2 CO 80% aq. EtOH 10% aq. Me2 CO H2 O

25 25 50 100

kF =kCl 1:0  10
6 1:6  10
4 3:2  10
3 2:9  10
2

bonding solvent increases the reactivity of a carbon–fluorine bond relative to the other carbon–halogen bonds [28, 30]. Table 5.4 shows the fluoride:chloride rate ratios for some arylmethyl halides, albeit under different conditions in some cases, but the differences in ratios are sufficiently large to suggest the trend towards an increasing ratio as the process changes from SN 1 to SN 2.

1

Acid catalysis

Catalysis by protonic acids accounts for the hydrolysis of fluorides, such as trityl fluoride [31], or elimination of hydrogen fluoride from various systems (Chapter 6), frequently being autocatalytic. The hydrolysis of benzyl fluoride is roughly proportional to the Hammett acidity function Ho [32], which is consistent with the scheme indicated in Figure 5.14 [1, 33]. Indeed, the decomposition of benzyl fluoride, on storage, may be violent [34]. PhCH2F

+

H+

PhCH2

F

H

PhCH2+

+

HF

½1, 33

Figure 5.14

Solvolysis of allylic fluorides may be acid-catalysed [35] and the influence of fluorine substituents at different positions is interesting. Solvolysis of 5.15A occurs where fluorine at the 1-position is able to stabilise an attached carbocation; but in the isomer 5.15B fluorine at the 2-position deactivates and solvolysis of 5.15B does not occur under conditions where 5.15A reacts (Figure 5.15). Similar hydrolysis of 1,2diethoxytetrafluorocyclobutene leads to the well-known, very stable, ‘squarate anion’ [36] (Figure 5.16a). Hydrogen iodide is very effective in replacing fluorine by iodine in fluoroalkanes [33] (Figure 5.16b). Cleavage of a carbon–fluorine bond can be induced by reaction with a Lewis acid (see Chapter 4, Section VIC). In Friedel–Crafts alkylations, alkyl fluorides are more reactive than the chlorides [37] with, for example, aluminium halides or boron halides as catalysts (Figure 5.17).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 130

130

Chapter 5 R
CHCH
CHF2 H

RCHF
CHCFH

+F

aq. HCOOH R −F

5.15A

H H

H2O

F

½35 R
CHCH
CHO

F R
CHF
CFCH2

R

H H

5.15B

H

Figure 5.15

2 O

OEt

O

OH

H2SO4

F

½36

2+ O

OEt

O

OH

O

O

Figure 5.16a

i

RF + HI

RI + HF

½33 i, R = 1-heptyl, 105 C, 10hr. (85%) R = cyclohexyl, 105 C, 1hr. (90%)

Figure 5.16b

BBr3

FCH2CH2Cl

C6H5CH2CH2Cl

Benzene

½37

Figure 5.17

Of course, this arises from a compensating greater strength of aluminium–fluorine or boron–fluorine bonds than the corresponding bonds to chlorine [D(A1–F) ¼ 615 kJmol
1 ; D(A1–Cl) ¼ 494 kJmol
1 ]. This difference also seems to be the driving force in the often very easy replacement of fluorine by chlorine, especially at allylic or benzylic positions, using aluminium chloride [38] (Figure 5.18). F

Figure 5.18

+

AlCl3

0 C

Cl

½38

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Nucleophilic Displacement of Halogen from Fluorocarbon Systems

2

131

Influence of heteroatoms on fluorine displacement

Oxygen or, particularly, nitrogen adjacent to a carbon–fluorine bond greatly increases reactivity towards nucleophiles. Hydrolysis of a, a–difluoro ethers occurs under acid conditions [39] (Figure 5.19). Orthoesters are produced by reaction with alkoxides; such reactions may, however, occur via initial elimination of hydrogen fluoride, rather than by direct nucleophilic displacement of fluoride [40] (Figure 5.20). CHF2CF2OC2H5

H2SO4

CHF2COOC2H5

½39

CHClFC(OC2H5)3

½40

Figure 5.19

CHClFCF2OC2H5

EtOH KOH

Figure 5.20

The exceptional ease of nucleophilic displacement of fluorine from ðC2 H5 Þ2 NCF2 CFClH and similar systems has been utilised as a general method for replacement of hydroxyl by fluorine (see Chapter 3, Section IVA, Subsection 3), and probably involves an SN 1 process with internal assistance to ionisation coming from the adjacent nitrogen [41] (Figure 5.21). F

Me N Me

C F

−F

−

F

Me

CF2H

N

C

CF2H

Me

etc

½41

O RCH2

H

Figure 5.21

The presence of C2H bonds in a perfluorinated system can, of course, have a profound effect, but the subsequent increase in reactivity usually stems from an elimination–addition rather than direct nucleophilic displacement of fluoride ion (see below).

B

Displacement of fluorine and halogen from unsaturated carbon – addition–elimination mechanism

When fluorine is attached to an unsaturated carbon atom, then a two-step displacement process can occur where the addition step may be rate-limiting (Figure 5.22) and it is probable that the importance of influence of the C–Hal dipole, in attracting the approaching nucleophile, has been under-appreciated. If the addition stage is rate-limiting, which is usually the case, polarity of the bond to carbon is probably the most important factor governing the activation energy required, since fluorine is sometimes displaced more easily than chlorine or the other halogens. For example, benzoyl fluoride reacts more readily with hydroxide than the corresponding

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132

Chapter 5

chloride [42, 43] (Table 5.5). However, the order of halogen mobility depends very much on the system and the order illustrated in Table 5.5 is Br > Cl > F. δ δ

Nuc

X

Nuc

F

Nuc

X

Addition

F

X

+

X

F

Elimination

Nuc

F

Figure 5.22 Table 5.5 Isopropanolysis of acid halides at 258 C [43] k2

Halogen mobility ratio Cl ¼ 1

8:4  10
10 5:1  10
6 2:7  10
3

1:6  10
4 1 5200

1:6  10
3 3:5  10
2

4:6  10
2 1

Compound C3 H7 CO2X X¼F X ¼ Cl X ¼ Br C4 F9 CO2X X¼F X ¼ Cl

It is reasonable to assume, therefore, that situations occur where the activation energy associated with the elimination step is comparable with that required for the addition stage. In these situations, overall reactivity is then also influenced by the strength of the carbon–halogen bond and, consequently, the stronger carbon–fluorine bond has a greater retarding effect than bonds between carbon and the other halogens.

1 Substitution in fluoroalkenes The usually greater reactivity of vinylic fluorine than vinylic chlorine is demonstrated in methanolyses of halonitrostyrenes [44] (Table 5.6), providing support for the two-step process with a rate-limiting addition stage outlined above.

Table 5.6 Nucleophilic substitution of p-nitrohalostyrenes using NaOMe at 258 C [44] p-NO2
C6H4

H

H

X

X¼F X ¼ Cl X ¼ Br


1

104 kðl:mol
1 s Þ 7.21 0.025 0.016

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Nucleophilic Displacement of Halogen from Fluorocarbon Systems

133

However, if both fluorine and chlorine are attached to the same vinylic carbon, the elimination stage of the mechanism becomes more important and, consequently, chlorine is selectively displaced, reflecting the greater leaving-group ability of chlorine compared with fluorine [45, 46] (Figure 5.23). C6H5 F3C

Cl

MeONa

F

C6H5

O-Me

C6H5

F

F3C

O-Me

+ F

F3C 96%

½45, 46

4%

Figure 5.23

Displacement of vinylic chlorine is predominantly stereoselective whereas, in some cases, substitution of fluorine can give a mixture of isomeric products. It has been argued that the fluorine-containing carbanionic intermediates are more stable and longer-lived than the corresponding chlorinated derivatives, thus allowing rotation to occur in the carbanionic intermediate before elimination of the halide, and enabling the formation of geometric isomers [47, 48]. The importance of the addition step, leading to a developing carbanion in the transition state, is made evident by the very wide range of reactivity in the series CF2 5CF2 , CF2 ¼ CFCF3  CF2 5CðCF3 Þ2 , the last of these being extremely susceptible to nucleophilic attack (Figure 5.24). Nuc

CF2C(CF3)2

Nuc
CF2CF(CF3)2

−F

Nuc
CFCF(CF3)2

Figure 5.24

Reactions of polyfluoroalkenes are discussed in Chapter 7.

2

Substitution in aromatic compounds

Nucleophilic substitution in highly fluorinated aromatic compounds will be dealt with in detail in Chapter 9, but it is worth noting here that, in common with most other nucleophilic aromatic substitutions [49], the processes are likely to involve two steps, with very little bond breaking in the rate-limiting transition state. In the classic work on 2,4-dinitrohalobenzenes with many nucleophiles, the ease of replacement of aromatic halogen is in the order F  Cl > Br > I [49, 50], arising from a slow first step ðk1 Þ and a fast second step ðk2 Þ, consistent with the scheme outlined in Figure 5.25. Of course, the nitro groups are extremely important in lowering the energy of the developing carbanionic transition state, leading to the intermediate complex 5.25A. Both oxygen and nitrogen nucleophiles react more rapidly with fluoroaromatics than corresponding sulphur and carbon nucleophiles, in accordance with Hard–Soft Acid–Base principles [51]. It should be remembered, however, that the situation can become more complex with, for example, base catalysis, where the rate of the second stage becomes important; under these rather unusual conditions, an order of replacement Br > Cl > F has been observed [52]. The second step may be rate-limiting in reactions of fluoroaryl systems with neutral amines [53]. Loss of halide ion from the intermediate complex is catalysed by base and is

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134

Chapter 5

much faster when fluorine is the leaving group compared with the other halogens, due to stronger hydrogen bonding between developing fluoride and the base [54] (Figure 5.26). For ortho-halonitrobenzenes, displacement of fluorine is more rapid than that of chlorine, due to lower steric requirements [55]. δ X δ

_ Nuc

Nuc

Nuc

X

NO2

NO2

NO2

k1

k2

½49, 50

k−1 NO2

NO2 X = F, Cl, Br, I

NO2

5.25A

Figure 5.25 X

H2RN NO2

NHR

X

NO2

NO2

RNH2

Base

½54 NO2

NO2

NO2

X = F, Cl, Br, I

Figure 5.26

Fluoroaromatics with electron-releasing substituents may be activated towards nucleophilic attack by complexation with chromium species [56] (Figure 5.27). H3C

F Cr(CO)3

LiCMe2CN CF3SO3H

H3C

CN

½56

Cr(CO)3

Figure 5.27

An oxidatively initiated nucleophilic substitution mechanism has been suggested to account for reactions with electron-rich aromatic substrates such as 4-fluoroanisole [57] (Figure 5.28). The foregoing discussion has outlined principles that can account for very wide differences in reactivities of the C2F bond. For example, while saturated perfluorocarbons like polytetrafluoroethene are relatively inert to nucleophiles, at the other extreme are perfluoroisobutene, which reacts with neutral methanol, and perfluoro-1,3,5-triazine, which is hydrolysed in moist air. As a note of caution, great care should be taken with the systems that are very reactive to nucleophiles and correspondingly potentially very toxic, although there is no good correlation between toxicity levels and reactivity towards nucleophiles. More will be said about some of these systems in later chapters.

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 135

Nucleophilic Displacement of Halogen from Fluorocarbon Systems

ArF ArF

+

−e

135

ArF [Nuc
Ar
F]

Nuc

½57 [Nuc
Ar
F] Ar
Nuc

+

Ar
Nuc Ar
F

+

Ar
Nuc

F

+

Ar
F

Figure 5.28

REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

C.A. Bunton, Nucleophilic Substitution at a Saturated Carbon Atom, Elsevier, Amsterdam, 1963. J. Hine and W.H. Brader, J. Am. Chem. Soc., 1953, 75, 3964. J. Hine and R.G. Ghirardelli, J. Org. Chem., 1958, 23, 1550. F.G. Bordwell and W. Brannen, J. Am. Chem. Soc., 1964, 84, 4645. T. Nakai, K. Tanaka and N. Ishikawa, J. Fluorine Chem., 1977, 9, 89. G.V.D. Tiers, J. Am. Chem. Soc., 1953, 75, 5978. X. Creary, Chem. Rev., 1991, 91, 1625. A.D. Allen and T.T. Tidwell in Advances in Carbocation Chemistry, ed. X. Creary, JAI Press, Greenwich, CT, 1989. F.G. Bordwell and C.A. Wilson, J. Am. Chem. Soc., 1987, 109, 5470. G. Kohnstam, D. Routledge and D.L.H. Williams, J. Chem. Soc., Chem. Commun., 1966, 113. D.J. Burton, J. Fluorine Chem., 1983, 23, 339. X.Y. Li, X. Jiang, H.Q. Pan, J.S. Hu and W.M. Fu, Pure Appl. Chem., 1987, 59, 1015. C. Wakselman, J. Fluorine Chem., 1992, 59, 367. V.I. Popov, V.N. Boiko and L.M. Yagupolskii, J. Fluorine Chem., 1982, 21, 365. A.E. Feiring, J. Fluorine Chem., 1984, 24, 191. A.E. Feiring, J. Org. Chem., 1983, 48, 347. Q.Y. Chen and Z.M. Qiu, J. Fluorine Chem., 1987, 35, 343. M. Medebielle, J. Pinson and J.M. Saveant, J. Am. Chem. Soc., 1991, 113, 6872. X.Y. Li, H. Pan and X. Jiang, Tetrahedron Lett., 1984, 25, 4937. C. Wakselman and M. Tordeux, J. Org. Chem., 1985, 50, 4047. C.-M. Hu and W.M. Huang in Fluorine Chemistry at The Millenium, ed. R.E. Banks, Elsevier, Amsterdam, 2000, p. 261. X.-T. Huang, Z.-Y. Long, and Q.-Y. Chen, J. Fluorine Chem., 2001, 111, 107. S.M. Igumnov, I.N. Rozhkov, S.I. Pletnev, Y.A. Borisov and G.D. Rempel, Bull. Acad. Sci. USSR, 1989, 38, 2122. A. Hasegawa, M. Shiotani and F. Williams, J. Chem. Soc., Faraday Discuss., 1978, 157. S.I. Pletnev, S.M. Igumnov, I.N. Rozhkov, G.D. Rempel, V.I. Ponomarev, L.E. Deev and V.S. Shaidurov, Bull. Acad. Sci. USSR, 1989, 38, 1892. D.D. MacNicol and C.D. Robertson, Nature, 1988, 332, 59. A.T. Umemoto, Chem. Rev., 1996, 96, 1757. R.E. Parker, Adv. Fluorine Chem., 1963, 3, 63. B.V. Tronov and E.A. Kruger, J. Russ. Phys. Chem. Soc., 1926, 58, 1270. J.A. Revetllat, A. Oliva, and J. Bertran, J. Chem. Soc., Perkin Trans. II, 1984, 815. A.K. Coverdale and G. Kohnstam, J. Chem. Soc., 1960, 3806.

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 136

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Chapter 5

32 C.G. Swain and E.T. Spalding, J. Am. Chem. Soc., 1960, 82, 6104. 33 M. Namavari, N. Satayamurthy, M.E. Phelps and J.R. Barrio, Tetrahedron Lett., 1990, 31, 4973. 34 S.S. Szucs, Chem. Eng. News, 1990, 68, 4. 35 T.J. Dougherty, J. Am. Chem. Soc., 1964, 86, 2236. 36 J.D. Park, S. Cohen and J.R. Lacher, J. Am. Chem. Soc., 1962, 84, 2919. 37 G.A. Olah, Friedel–Crafts and Related Reactions, Wiley-Interscience, New York, 1964. 38 R.F. Merritt, J. Am. Chem. Soc., 1967, 89, 609. 39 J.A. Young and P. Tarrant, J. Am. Chem. Soc., 1950, 72, 1860. 40 P. Tarrant and H.C. Brown, J. Am. Chem. Soc., 1951, 73, 1781. 41 V.A. Petrov, S. Swearingen, W. Hong and W.C. Petersen, J. Fluorine Chem., 2001, 109, 25. 42 C.G. Swain and C.B. Scott, J. Am. Chem. Soc., 1953, 75, 246. 43 J. Miller and Q.L. Ying, J. Chem. Soc., Perkin Trans. II, 1985, 323. 44 G. Marchese, F. Naso and G. Modena, J. Chem. Soc. (B), 1969, 290. 45 D.J. Burton and H.C. Krutzsch, J. Org. Chem., 1971, 36, 2351. 46 H.F. Koch and J.G. Koch in Fluorine-containing Molecules. Structure, Reactivity, Synthesis and Applications, ed. J.F. Liebman, A. Greenberg and W.R. Dolbier, VCH Publishers, New York, 1988, p. 99. 47 Y. Apeloig and Z. Rappoport, J. Am. Chem. Soc., 1979, 101, 5095. 48 B.E. Smart in The Chemistry of Functional Goups, Supplement D, ed. S. Patai and Z. Rappoport, John Wiley and Sons, New York, 1983, p. 603. 49 J. Miller, Aromatic Nucleophilic Substitution, Elsevier, Amsterdam, 1968. 50 V.M. Vlasov, J. Fluorine Chem., 1993, 61, 193. 51 F.G. Bordwell and D.L. Hughes, J. Am. Chem. Soc., 1986, 108, 5991. 52 T.J. Broxton, D.M. Muir and A.J. Parker, J. Org. Chem., 1975, 40, 3230. 53 N.S. Nudelman, J. Phys. Org. Chem., 1989, 2, 1. 54 E.T. Akinyela, I. Onyido and J. Hirst, J. Chem. Soc., Perkin Trans. II, 1988, 1859. 55 T.O. Bamkole, J. Hirst and E.J. Udoessien, J. Chem. Soc., Perkin Trans. II, 1973, 110. 56 F. Rose-Munch, L. Mignon and J.P. Sanchez, Tetrahedron Lett., 1991, 32, 6323. 57 L. Eberson, L. Jonsson and L.G. Wistrand, Tetrahedron, 1982, 38, 1087.

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 137

Chapter 6

Elimination Reactions

Since eliminations cover a very wide spectrum of chemical reactions, this chapter is a selective discussion of the subject. The mechanistic basis of b-eliminations is discussed, largely with reference to dehydrohalogenation, and a variety of a-eliminations are included here. Other eliminations, such as dehalogenation, are described throughout later chapters with reference to specific syntheses.

I A

b-ELIMINATION OF HYDROGEN HALIDES Effect of the leaving halogen

Effects arising from the halogen atom that is eliminated during b-elimination of hydrogen halide may be summed up (Figure 6.1) as: (a) b-halogen has an acidifying influence on the adjacent hydrogen; and (b) ease of elimination will vary with the strength of the carbon–halogen bond and the ability of halogen to accommodate a negative charge. The combination of these effects is likely to be in the order F < Cl < Br. Of course, elimination will also be solvent-dependent. Clearly, b-elimination of hydrogen fluoride should proceed via a transition state that will be very carbanionic in character, and at a rate slower than corresponding hydrogen halide eliminations since carbon–halogen bond breaking is involved in the rate-determining step. These effects are well illustrated in eliminations from 2-phenylethyl derivatives [1, 2] (Table 6.1). β C

α C

H

X

B

C

C

+

+

BH

+

X

X = Halogen

Figure 6.1

Eliminations from fluorides are often autocatalytic [3], due to assistance in ionisation by hydrogen bonding between the leaving fluoride ion and hydrogen fluoride produced in the reaction (Figure 6.2). As a consequence, fluorides can sometimes be more stable in even slightly alkaline solution than in the pure state [3]. Table 6.1 Relative rates of elimination of HX from PhCH2 CH2 X [1, 2] Substrate

Reaction conditions

X¼F

X ¼ Cl

X ¼ Br

PhCH2 CH2 2X PhCHBrCF2 2X

EtONa, EtOH, 308 C EtONa, EtOH, 258 C

1 1

68 4
105

4100 3
107

Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

137

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138

Chapter 6 δ− F

δ+ C

C

H

F

C

+

C

−

HF2

½3

H

Figure 6.2

Elimination of HBr in preference to HF from the cyclohexane derivative 6.3A further demonstrates the greater leaving-group ability of other halogens over fluorine [4] (Figure 6.3). Br + F

F

F

½4

(9:1)

6.3A

Figure 6.3

However, in some cases, HF is eliminated in preference to dehydrobromination, e.g. in the succinic acid series [5, 6] (Figure 6.4). In these less common processes, the transition state has significant carbanion (E1cB-like) character, and the products are probably governed by the relative stabilities of the possible carbanionic transition states, 6.5A and 6.5B (Figure 6.5), where a fluorine atom situated b to a developing carbanion centre, as in 6.5B, is more stabilising than when directly attached, as in 6.5A. This effect is also seen in eliminations from dihaloacenaphthenes [7]. Br

F

Br

½5, 6 HO2C

CO2H

HO2C

CO2H

Figure 6.4 B

B Br HO2C

H δ+ δ−

δ+H

F

Br

CO2H

HO2C

6.5A

δ− 6.5B

F CO2H more stable

Figure 6.5

B Substituent effects A spectrum of transition states is possible for eliminations [8], varying from transition states with considerable double-bond character, 6.6A, through those with increasing amounts of charge developed on the b-carbon atom, 6.6B, until an E1cB mechanism is observed [9] when the b-hydrogen has been made sufficiently acidic to be removed, leaving a carbanion (Figure 6.6). Base-catalysed hydrogen/deuterium exchange is still probably the only definitive probe for the ElcB process in which H/D exchange occurs in the starting material at a rate faster

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139

than the second elimination stage (Figure 6.7), although internal return can be significant, which then leads to an under-estimation of kinetic acidity [9]. Indeed, it has been suggested that a hydrogen-bonded carbanion may be an intermediate, rather than a transition state [10]. C

C

X

C

δ−

C

X

H

Hδ+

6.6A Concerted

6.6B E1cB - like

½9

Figure 6.6 Base (−H+) C

C

X

Solvent (+D+) C

C

C

X

Solvent (+H+)

H

C

X

½9

D

Internal Return

C

C

X

C

C

+

X−

Figure 6.7

Highly halogenated alkanes often undergo base-catalysed H/D exchange at rates faster than elimination [11]; for example, H/D exchange for PhCHClCF2 Cl has been measured to be 1:65
102 l:mol1 s1 [9]. However, in a related system, PhCHClCF3 , no H/D exchange is observed but isotope effects suggest that the mechanism is also a two-step E1cB process in which elimination of chloride ion from the intermediate carbanion is much faster than deuteration [12].

C

Regiochemistry

In concerted E2 eliminations from monofluorides the orientation of elimination is controlled by the relative acidities of b-hydrogen in a process that is consistent with a poor leaving group and a transition state with high carbanionic character of the b-carbon atom [13] (Figure 6.8). H C3H7CH2

C F

CH3

NaOMe

C4H9

MeOH

H

C3H7

H

H

½13

+ H 69%

H

CH3 21% C3H7

CH3

+ H

H 9%

Figure 6.8

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140

Chapter 6

The orientation of elimination of hydrogen halides from more highly fluorinated systems is also governed by the relative acidities of hydrogen atoms within the molecule, and therefore the relative stabilities of the intermediate carbanions, as well as the mobility of the leaving halogen, which is generally in the order I > Br > Cl > F. The examples in Figure 6.9 illustrate these points, in which the most acidic proton and the best halogen leaving group are eliminated preferentially [14–16]. KOH

CF3CH2CHBrCH3

EtOH

CHCl2CCl2CHF2 CCl3CH2CF2Cl

Aq. KOH

CF3CH
CHCH3

½14

CCl2
CClCHF2

½15

CCl2
CHCF2Cl

½16

Figure 6.9

In addition to C2H acidity, elimination may also be controlled by the mobility of fluorine from carbon, which generally decreases in the series 2CF > 2CF2 > 2CF3 , as can be seen in the examples in Figures 6.10 and 6.11. Where there is a choice, the most stable fluoroalkene, in which the number of vinylic fluorines is at a minimum (see Chapter 7), is the predominant product. CF3CF
CHF

CF3CHFCHF2

+

70%

CF3CH
CF2

½17

30%

Figure 6.10 RFH

RF KOtert-Bu

½18

−10 C RFH RFH

= CF2CFHCF3

RF RF

=

CF
CFCF3

Figure 6.11

D Conformational effects In many cases, elimination of hydrogen halide via an anti-coplanar transition state is observed [19] (Figure 6.12) in what is commonly regarded as the most favourable process [20, 21]. However, overall syn elimination is more common than was once thought; a variety of factors may be responsible. The ratio of products arising from syn/anti elimination can depend on the reaction medium, e.g. syn elimination appears to be enhanced by a less polar medium, and this has led to the suggestion that a concerted cyclic process involving the base may be involved [19] (Figure 6.13).

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141

F C5H11

C5H11

H

C5H11

H

t-BuOK THF

F

(only alkene formed) C5H11

½19

F

H F C5H11 F

C5H11

H

H

t-BuOK

C5H11

(only alkene formed)

THF

F

C5H11

H

Figure 6.12

X Y H

X Y F

B

X

X

Y

Y

+

M M

B

BH

+

B

= Base

MF

½19

M = Metal

Figure 6.13

It has been suggested that favourable hydrogen-bonding interactions between R and trifluoromethyl in an E1cB-like transition state, 6.14B, could account for the formation of the least thermodynamically stable isomer, 6.14C, from 6.14A; 6.14C is converted to 6.14D on heating with caesium fluoride [18] (Figure 6.14).

RCF2CFHCF3

i

F

R

F

F

R

CF3

6.14C F3C

6.14A

F

F

½18

6.14B ii

R = Adamantyl

i,

R

F

F

CF3

KOtert-BuOH, tert-BuOH, 0 C

ii, CsF, Tetraglyme, 200 C

6.14D

Figure 6.14

The preferential syn elimination of hydrogen fluoride, in preference to elimination of hydrogen bromide, from 6.15A is particularly surprising [22] (Figure 6.15). It is not clear how much the true preference for a gauche relationship between a fluorine substituent and an adjacent electron-withdrawing centre [23] will have on the ease of elimination of hydrogen fluoride, but it is clearly an area of interest.

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142

Chapter 6 F

F CO2Et

H H

CO2Et

H H

CO2Et

Br

EtO2C

H

CO2Et

i syn

½22 EtO2C

Br

Br

6.15A i, NaOH, H2O

anti

Figure 6.15

E

Elimination from polyfluorinated cyclic systems

Tatlow and his co-workers conducted an extremely comprehensive programme of syntheses and structure derivations of a series of fluorinated cycloalkanes [24], and concluded that the reactivity of the system, as well as the orientation of the cycloalkene produced, are similarly influenced by electronic factors which have been outlined in the preceding sections of this chapter. Anti elimination is generally the more favourable process but conformational effects may make the syn/anti rates nearly comparable. Elimination from the cyclohexanes 6.16A and 6.16B illustrates the balance between electronic and conformational effects [25]. Anti elimination is possible from 6.16A, involving removal of fluoride from >CHF rather than >CF2 since in this case electronic (the carbon–fluorine bond in CFH is weaker than in CF2 ) and conformational effects (H and F are anti-periplanar) are in concert (Figure 6.16). In contrast, anti elimination from 6.16B can only occur with elimination of fluoride from the more stable > CF2 position and therefore anti and syn eliminations occur together. F

F H

H

F

aq. KOH

F

F F

F

H

F

F

F F

F 6.16A

F

½25

F

H

H

F

aq. KOH

F

F F

F F

F

F

+

F

F

F

H 6.16B

Figure 6.16

Electronic factors dominate reactivity in the series shown in Figure 6.17; in this series, qualitatively, the order of reactivity indicated has been established [26]. There is probably a relationship between reactivity and the number of acidifying b-fluorine

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143

atoms, which decreases as shown, and this is supported by the product from the fluorocycohexane (Figure 6.18), where exclusive removal of the more acidic hydrogen occurs [26]. H F

H >

H

F

F

H

H

>>

F

H

H H H H

½26

Figure 6.17

F

F H H H

H aq. KOH

F

½26 H

Figure 6.18

In the cyclopentane series, electronic factors remain unchanged but differences in conformation effects may be significant. A coplanar arrangement of atoms in the transition state is energetically favourable; this can, of course, be accommodated in anti elimination from cyclohexane systems, but only in syn elimination from highly fluorinated cyclopentanes (Figure 6.19). However, anti elimination is still a favourable process [27] for these systems and electronic factors often outweigh conformational effects in determining the orientation of elimination. Repulsion F F

F F H

Base

H

Base Cyclohexane

Cyclopentane

Figure 6.19

The reactions of cyclopentanes 6.20A and 6.20B with aqueous alkali both give the same cylopentene by anti and syn elimination respectively, with only traces of by-products arising from syn elimination from 6.20A or anti elimination from 6.20B (Figure 6.20). Inward syn elimination occurs from 6.20B, giving the cyclopentene in 86% yield, and this is a further indication that removal of fluoride from > CHF is easier than from > CF2 (Figure 6.20) In the cyclobutane series [28] (Figure 6.21) syn and anti eliminations from 6.21A and 6.21B proceed again at much more nearly comparable rates than from corresponding cyclohexane systems.

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144

Chapter 6 H

H H

F

−HF

H −HF

F

H

F

H

H

H

6.20A

6.20B

Figure 6.20 H

H

H F

F

aq. KOH

F

+

F

F

½28

F F

H 6.21A cis 6.21B trans

Figure 6.21

II b-ELIMINATION OF METAL FLUORIDES b-Elimination of two halogen atoms is a frequently used process in the synthesis of alkenes and alkynes, using a variety of conditions, and examples will be given later (see Chapter 7). Normally, fluorine is not easily removed by this process, although there are a number of cases where defluorination has been achieved, for instance in the preparation of fluoroaromatic compounds (Chapter 9). However, a feature of the chemistry of fluorocarbon organometallic compounds is that decomposition by a- or b-elimination of a metal fluoride is very common. The ease with which such decompositions occur is very variable and factors such as the strength of the metal–fluorine bond being formed, the type of carbon–fluorine bond being broken, the mechanism of the process and whether the metal has an available empty orbital to aid migration of fluorine are all important in affecting the elimination. Fluorocarbon organometallic reagents will be discussed separately in Chapter 10, where these points will be illustrated; only examples of some eliminations from organolithium derivatives of polyfluoroalkanes and polyfluorocycloalkanes will be referred to here. Perfluoroalkyl-lithium derivatives are thermally unstable and their use in organic synthesis has been limited by competing b-elimination processes [29]. Pentafluoroethyllithium has a half-life of around 8 h at 788 C [30]. In complete contrast, perfluorinated bridgehead lithio derivatives are much more stable since, in these cases, elimination of LiF would contravene Bredt’s rule and would, therefore, be a higher-energy process. Consequently, perfluoroadamantyl-lithium is stable at 08 C for several days [31] (Figure 6.22).

Figure 6.22

H

Li

F

F

½31

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Elimination Reactions

145

Nevertheless, evidence that bridgehead alkenes or diradical species are generated by decomposition of 6.23A was obtained by trapping with furan [24, 32, 33] (Figure 6.23).

F

CH3Li

F

F

furan 25−30 C

H

½24, 32, 33

O

Li 6.23A

Figure 6.23

Surprisingly, the bicyclo[2.2.2]octane derivative (Figure 6.24) is much more stable [33] than the analogous norbornyl system 6.23A, and this has been attributed to the additional stabilising influence of the extra CF2 group, since there is no obvious stereochemical reason for the considerable difference in the rates of decomposition. This is a quite dramatic illustration of how electronic effects of groups which are apparently remote from the reaction centre can have a considerable effect on reactivity; this effect, while being well documented for other areas of organic chemistry, is not much in evidence in reactions of organic fluorine compounds.

F Li

Figure 6.24

A related b-elimination occurs when alkali-metal salts of perfluoroalkanecarboxylic acids are pyrolysed [34] (Figure 6.25). The most likely process involves decarboxylation with elimination of fluoride ion from the resultant carbanion. Indeed, the method can be very useful for the synthesis of perfluoroalkenes (Chapter 7), the most important example of which is shown in Figure 6.26 and is used in the production of fluorinated membranes [35]. −

CF3CF2CF2CO2

Na

+

∆, −CO2

F F3C

C

CF2

½34

F

CF3CF
CF2

+

NaF

Figure 6.25

Novel chemistry that was initiated by Nakai and co-workers [36, 37] involves elimination of hydrogen fluoride from the tosylate of trifluoroethanol, followed by reaction of the intermediate with appropriate electrophiles (Figure 6.27). A wide range of approaches to the synthesis of difluoromethylene derivatives has ensued.

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146

Chapter 6 O F

C

CF(CF3)OCF2CF(CF3)OCF2CF2SO2F

½35

Heat, Na2CO3 CF2
CFOCF2CF(CF3)OCF2CF2SO2F

Figure 6.26

− CF3CHOTs

i CF3CH2OTs

CF2
CHOTs

i, LDA, THF, −78 C ii, n-BuLi, R3B

Electrophiles

½36, 37

ii CF2
CLiOTs OTs

R

CF2
C

CF2
C BR2

Electrophiles B R

R R Various products.

Figure 6.27

A simple alternative approach to the synthesis of difluoromethylene compounds involves electron transfer from metals to carbon–oxygen or carbon–nitrogen double bonds [38, 39] (Figure 6.28). O

O R

−F

−

i F3C

( +1e)

F3C

− O

−

R

F2C

( +1e)

½38, 39 R

R = Alkyl or Aryl

i, Mg (2 equiv.), TMS-Cl (4 equiv.), 0 C, 30 min. ii, R1R2CO ii Product

OTMS F2C R

Figure 6.28

Reactions of lithium derivatives and Grignard reagents from polyfluoroalkenes or polyfluoroaromatic compounds are often complicated by eliminations but are generally much more useful in synthesis than polyfluoroalkane derivatives. Generation of arynes is discussed later (see Chapter 9).

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III

147

a-ELIMINATIONS: GENERATION AND REACTIVITY OF FLUOROCARBENES AND POLYFLUOROALKYLCARBENES

Fluoromethylene and polyfluoroalkylmethylene units can be introduced into various molecules by a variety of processes that, overall, involve a-elimination from the original fluorocarbon system. The processes themselves are carbenoid but may not necessarily involve carbene intermediates. There are many carbenoid procedures available for the insertion of fluorine-containing units and they can be roughly divided into the following four types [40, 41]. (1)

Decomposition of carbanions (Figure 6.29). X

C

−

C

X

Figure 6.29

(2)

Elimination of metal and non-metal fluorides (Figure 6.30). F C

+ MF

C

M

Figure 6.30

(3)

Fragmentation reactions (Figure 6.31). C X

C

C

X

Y

C

C

+

Y

C

Figure 6.31

(4)

Decomposition of diazo compounds (Figure 6.32). N C

N2

or

N2

C

+

C

N

Figure 6.32

Examples of each of these types follow.

A 1

Fluorocarbenes From haloforms

The classic work of Hine and co-workers [42, 43] established that carbenes could be generated by base hydrolysis of haloforms and that the process could be divided into two steps (Figure 6.33).

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148

Chapter 6

CHXYZ

−

+

OH

CXYZ

X

CXYZ

C

+

H2O

Y +

½42, 43 −

Z

Figure 6.33

The deprotonation step was deduced from H/D exchange studies and the second stage from a steady-state treatment of the overall rates of hydrolysis. Stabilisation of the intermediate carbanions by halogen follows the order I > Br > Cl > F (Chapter 4, Section VII) and loss of halide ion in stage 2 is in the order of leaving group ability, I > Br > Cl > F. Therefore, it was possible to conclude that the effect of fluorine on the stability of carbenes is in the order F > Cl > Br > I [42]. Fluorine is relatively poor at stabilising directly attached carbanions; however, it appears to be the best of the halogens at stabilising carbenes, and consequently elimination of HZ (Figure 6.33) may become concerted if X is a sufficiently good leaving group. In eliminations of HBr from CHBrF2 no H/D exchange is observed [44], which could indicate a concerted process, but elimination of bromide ion may, in this case, be much faster than deuteration (cf. b-eliminations, Section I) and so a two-step process cannot be ruled out. A number of different bases, usually KOH or NaOH [45] with a phase-transfer catalyst [46] or crown ether [47], have been used for generating carbenes which can be trapped by nucleophilic species such as alkoxides, thiolates and, more usually, alkenes. This approach to carbene generation is still popular due to the low cost and the ease of handling the reagents used; some examples are given in Figure 6.34 [45, 46, 48].

F CH2Br2

+

CF2Br2

H3C

CH3

H3C

CH3

i

+

CH3

H3C

CH3

i, Bu4N HSO4, 60% KOH

F H3C

CH3

H3C

CH3

i + CHFCl2

Cl

H3C

CH3

H3C

CH3

Br

½46

+

−

i, 50% NaOH, CH2Cl2, Et3N CH2Ph Cl

Figure 6.34

F

i

CFHBr2

½45

43%

i, NaOH, tetraglyme, 95 C

+

½48

+ 2KBr + CBr4 + 2H2O

−

+

F

H3C

90%

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Elimination Reactions

2

149

From halo-ketones and acids

The formation of dihalocarbenes by decomposition of trihaloacetate anions is well known and is usually formulated as involving two steps (Figure 6.35) but, of course, the process could be concerted. O



ClCF2C




ClCF2 + CO2

O

ClCF2

FCF + Cl

Figure 6.35

It is found that decarboxylation of dichlorofluoroacetate [49] gives about 70% of CCl2 FH via competitive abstraction of a proton from solvent by the intermediate  CCl2 F anion, whereas chlorodifluoroacetate [50] gives very little CClF2 H, suggesting either that chloride ion loss in this case is faster than protonation, or that the process is concerted. Decarboxylation procedures have been widely used, mainly for the preparation of fluorocyclopropyl derivatives as illustrated in Figure 6.36 [51, 52]. F Ph H

H

i

F

Ph CH3

CH3

88%

½51

H

OAc

OAc

i, ClF2CCOO− Na+, diglyme, reflux

C8H17

i OAc

F C8H17 H

F

½52 OAc

i, ClF2CCOO− Na+, diglyme, reflux

Figure 6.36

In similar processes, base-induced cleavage of halogenated ketones has been used to prepare cyclopropane derivatives [53] (Figure 6.37).

3

From organometallic compounds

Trifluoromethyl-lithium, prepared by metal/halogen exchange, is unstable; its decomposition probably involves generation of difluorocarbene, which dimerises [54] (Figure 6.38). Elimination of bromine from dibromodifluoromethane is readily achieved, and various trapping experiments have been carried out with difluorocarbene from this source [55] (Figure 6.39).

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150

Chapter 6 O

O

i H3C

CFCl2

C

H3C

CFCl2

CFCl2

½53

H −Cl

i, NaH, MeOH F Cl

CFCl

60%

Figure 6.37 i CF3I

CF3Li

−LiF

CF2

F2C

CF2

½54

i, CH3Li, −45 C

Figure 6.38

CF2Br2

n-BuLi

CF2BrLi

−LiBr

F CF2

½55

F

Figure 6.39

Perfluoroalkyl anions, which form carbenes upon subsequent elimination of afluorine, may be generated by cleavage of the carbon–tin and carbon–mercury bonds in, for example, (trifluoromethyl)trimethyltin [56] and phenyl(trifluoromethyl)mercury [57] (Figure 6.40) under very mild conditions. Carbenes may be generated from I

−

Me3Sn

CF3

−

CF3 +

−

Me3Sn-I

−F

½56

CF2

F F 89%

F

i + PhHgCF3

F

+ −

i, NaI, Bu4N I , 18-crown-6, 80 C

Figure 6.40

56%

½57

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Elimination Reactions

151

perfluoroalkyl anions which, in turn, may be displaced from, for example, tin, mercury or silicon by halide ions. Here the driving force is the strength of the new bond to halogen being formed. A combination of zinc and CF2 Br2 can be used to add difluorocarbene to relatively reactive alkenes [58] (Figure 6.41a). F Ph

i

Ph

H3C

F 71%

½58

H3C i, CF2Br2, Zn, I2 (cat), rt

Figure 6.41a

Remarkably, ðCF3 Þ3 Bi generates difluorocarbene at low temperatures in the presence of aluminium trichloride [59] (Figure 6.41b). i (CF3)3Bi

ii

F

[CF2] F

½59

i, AlCl3, −30 C ii, Cyclohexene

Figure 6.41b

4

From organophosphorous compounds

Difluorocarbene can be conveniently generated at room temperature by the addition of fluoride ion to bromodifluorophosphonium bromide and, provided that the solvents are scrupulously dry, can be trapped by alkenes [60], dienes [61] and cycloalkenes [62] (Figure 6.42). The phosphonium salt may be generated in situ, allowing cyclopropanation to be carried out in a one-pot process [60] (Figure 6.43). Addition of 18-crown-6 to the reaction medium enhances the solubility of the metal fluoride and allows cyclopropanation of less nucleophilic alkenes and alkynes to be performed [63] (Figure 6.44).

5

Pyrolysis and fragmentation reactions

Pyrolytic a-elimination of HCl from CHClF2 is the basis for the manufacture of tetrafluoroethene on an industrial scale [64] (Figure 6.45). A carbene intermediate has been proposed for the formation of hexafluorobenzene by pyrolysis of CHFCl2 and CHFBr2 [65], whilst difluoroacetylene is the suggested intermediate in the corresponding pyrolysis of CFBr3 [66] (Figure 6.46). Hexafluoropropene oxide (HFPO) [67] fragments exclusively by a reversible process at high temperature to give trifluoroacetyl fluoride and difluorocarbene only [68] (Figure 6.47). Cyclopropanation of electron-deficient alkenes is also possible, as shown in Figure 6.48, but molecular rearrangements at the high temperature required for HFPO decomposition may reduce the yield of the desired product [69–72].

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152

Chapter 6 F +

Br

[Ph3PCF2Br]

−

+ CsF +

H3C

CH3

H3C

CH3

i

CH3

H3C

CH3

i, diglyme, rt

+

+

[Ph3PCF2Br]

F

i

−

Br

F

H3C

½60

79%

F

F

F

+

½61

i, CsF, triglyme, rt 38%

+

+

[Ph3PCF2Br]

Br

22%

F

i

−

½62

F i, KF, triglyme, rt

92%

Figure 6.42

F H3C +

Ph3P + CsF + CF2Br2

F

H3C

i

H3C

½60

H3C i, diglyme, rt

66%

Figure 6.43

PhC

CH

+

+

[Ph3PCF2Br]

Br

−

F

i Ph

F

H

½63

i, KF, 18-crown-6, glyme, rt 79%

Figure 6.44

CHClF2

Figure 6.45

> 650 C 0.5 atm.

CF2

F2C

CF2

½64

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Elimination Reactions i

CHFCl2

C6F6

+ CFCl3 + CFCl
CFCl + CFCl2CFCl2

153

½65

i, Pt, 700−750 C i

CFBr3

C6F6

½66

35%

i, Pt, 640 C

Figure 6.46

O

F F3C

F

O

165−185 C

+ F3C

F

½68

CF2

F

Figure 6.47

F F

F

H

F

F

i H F

½69

65%

F F

i, HFPO, 185 C, 6 h

F

H

F F

F

i

F

F

F

½70

63%

F

H

H

H

F

F

i, HFPO, 175 C

F

CF3

•

i

F3C

CF3 F

½71

52% CF3

F

F

i, HFPO, 175 C

F F

Cl i

F

F Cl

Cl

+

Cl 50%, 1:1

i, HFPO, CaCO3, 185 C

Figure 6.48

F

Cl Cl

½72

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154

Chapter 6

Pyrolysis of various phosphorane, e.g. ðCF3 Þ2 PF2 [73], and fluoroalkylated tin compounds [74] has been used to generate difluorocarbene. Diazirines decompose to give carbenes by either photolysis or pyrolysis [75] (Figure 6.49). F

F +

F

N

F

N

135 C 85%

½75

Figure 6.49

Remarkably, tetrafluoroethene [76] and even PTFE [77] (Figure 6.50) may be used as sources of difluorocarbene, if sufficiently high temperatures are used. Cl F

CF3

CF2

Cl

½76

i

F

F

+

F

F

F

F

CF3

i, CF2
CF2, 640 C F3C

CF3

i

F

F

+

N

½77

N

N i, (CF2)n, 550 C

isomers

Figure 6.50

Reactions of arc-generated carbon with fluorocarbons lead to CF, which reacts in ways resembling carbenes to give a variety of products [78, 79] (Figure 6.51). +

C

CF4

F

C

CF3

CF2

+

CF

N

F

F

F +

N

½78

CF2

½79

N

Figure 6.51

However, there are still no general methods for the preparation of fluorocarbene, CFH [41].

B Polyfluoroalkylcarbenes A useful source of perfluoroalkylcarbenes is the corresponding diazoalkane, or diazirine [80, 81], which have been obtained by a variety of routes (Chapter 8). Confirmation that bis(trifluoromethyl)carbene is produced in the pyrolysis of these species comes from the observation that, at low pressures, hexafluoropropene is obtained; it results from an internal 1,2-fluoride shift in the intermediate carbene [80] (Figure 6.52).

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 155

Elimination Reactions

F3C N2 F3C

250 C Low pressure

CF3CF=CF2

(CF3)2C=C(CF3)2

+

155

½80

Figure 6.52

Insertion reactions [81], alkene additions [82] and even additions to benzene and hexafluorobenzene [83] have been observed using these sources of carbenes, as shown in Figure 6.53. F3C

N2

H

F3C

N2 +

F

hν

+

H3C

CH3

H3C

CH3

F3C N2

+

F

CF3CH2

76%

F3C 170 C

150 C

½81

F

H3C

CH3

H3C

CH3

CF3

F

F3C

30%

20%

½82

½83

CF3

Figure 6.53

However, many reactions of bistrifluoromethyldiazoalkanes may involve formation of an intermediate pyrazoline followed by loss of nitrogen, rather than a carbene intermediate: a cyclic adduct has been isolated from reaction of bis(trifluoromethyl)diazomethane with but-2-yne, which then loses nitrogen on pyrolysis [80] (Figure 6.54).

N2 F3C

CH3

H3C

F3C + CH3C

CCH3

CF3

N N

½80

CF3 400C −N2

F3C

H3C

CF3

CH3

Figure 6.54

Organo-metallic or -metalloid reagents provide efficient routes to fluoroalkylated carbenes; difluoromethylfluorocarbene (6.55A) is readily generated by a general route which involves the pyrolysis of fluoroalkylsilicon compounds [84] (Figure 6.55).

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 156

156

Chapter 6 HSiCl3 + C2F4

hν

SbF3

CHF2CF2SiCl3

CHF2CF2SiF3

½84

150 C

(CH)3CCHFCHF2

(CH3)3CH

F2HC

61%

C

F

+ SiF4

6.55A

Figure 6.55

The mercurial C6 H5 HgCFBrCF3 serves as a useful transfer agent for CF3 CF [85] (Figure 6.56). + C6H5HgCFBrCF3

F

160 C

87%

C6H6

½85

CF3

Figure 6.56

C Structure and reactivity of fluorocarbenes and polyfluoroalkylcarbenes 1 Fluorocarbenes The existence of two possible and opposing effects arising from fluorine attached to the carbon of a carbene produces a dichotomy analogous to that which occurs in fluorocarbocations (Chapter 4, Section VI). The inductive effect of fluorine should make the carbon atom, which is already electron-deficient, even more electrophilic (6.57A in Figure 6.57), but the possibility of p-bonding (6.57B) between fluorine and a vacant orbital on carbon could also occur. F

δ+ C 6.57A

δ− F

F

C

F

F

C

F

6.57B

Figure 6.57

On the basis of spectroscopic and thermodynamic data, it has been concluded that p-bonding is significant in difluorocarbene [86] and to a degree which accounts for the fact that it is surprisingly stable and relatively unreactive compared with CH2 and other carbenes [86]. That the balance between the two effects is clearly dominated by p-bonding is illustrated by the relative reactivities of various carbenes with different alkenes; it is concluded that electrophilicity decreases in the series CH2 > CBr2 > CCl2 > CFCl > CF2 and CH2 > CHF > CF2 . Indeed, CF2 is considered to be amphiphilic [87]. Of course, carbenes can exist as either a singlet or triplet in the ground state, and the calculated energy differences between these two states (DEST ¼ ET  ES ) for several different carbenes are given in Table 6.2. Electron-withdrawing substituents lower orbital energies and we have noted the stabilising effect of perfluoroalkyl groups on radicals

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Elimination Reactions

157

Table 6.2 Calculated energy difference between singlet and triplet states of carbenes, DEST [89, 90] Carbene

DEST ðkJmol1 Þ

CH2 CHF CF2 CðCF3 Þ2

246 142 808 313

(Chapter 4) and their strongly destabilising effect on carbocations. In parallel with these observations, a trifluoromethyl group clearly enhances the stability of the triplet state (Table 6.2). Conversely, fluorine directly attached to the carbene centre strongly favours the singlet state, which, of course, contains a vacant orbital that is able to interact strongly with the non-bonding electron pairs on fluorine. However, CFCl and CFBr are also found to have singlet ground states [88]. The stereochemistry of reactions between carbenes and alkenes is determined by the states of the carbenes (when generated), whereby singlet carbenes react in a stereospecific one-step concerted process whilst triplet carbenes lead to a mixture of products via a diradical intermediate (Figure 6.58). Consequently, since fluorocarbenes are singlets in the ground state (Table 6.2), cyclopropanation of alkenes is often stereospecific [91] (Figure 6.59) (for more examples, see Sections A and B). R1

R2

R3

R4

F

F

singlet CF2 R2

R1 R3

R4

triplet CF2

R1 R3

R2 R4

F

Spin Inversion

CF2

R1 R3

F

F +

R2

R1 R3

R4

F R4 R2

Figure 6.58 F

C2H5

F

Me3Sn-CF3 C2H5

NaI

H

C2H5 H

74%

½91

C2H5

Figure 6.59

The selectivity of carbenes has been qualitatively estimated by a series of competition reactions between various carbenes and mixtures of different alkenes; it is found that electrophilic carbenes react preferentially with the most electron-rich alkene present [87, 92]. Fluorocarbenes, being less reactive, give rise to fewer products from C2H insertion reactions than CCl2 [91] (Figure 6.60). However, selectivity may be temperaturedependent [93, 94].

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 158

158

Chapter 6

Cl CCl2 CCl2H

O

O

Cl

½91

+ O (1 : 1)

CF2 F

F

O

Figure 6.60

2 Polyfluoroalkylcarbenes Electronic effects in bispolyfluoroalkylcarbenes (6.61A) are clearly defined, in that the already electron-deficient carbon is made even more electrophilic by the strong electron withdrawal by polyfluoroalkyl groups (Figure 6.61). Polyfluoroalkylfluorocarbenes (6.61B) are, however, an intermediate situation with the possibility of compensating p-bonding, as described earlier. δ− RF

δ+ C

RF

δ− RF

6.61A

δ+ C

F

6.61B

Figure 6.61

The extremely electrophilic nature of bis(trifluoromethyl)carbene has already been illustrated by the formation of addition products, even with hexafluorobenzene [83] (Section IIIB), and the high reactivity results in more side-reactions, such as insertion into C2H bonds, than with difluorocarbene (Figure 6.62). C(CF3)2H

C(CF3)2H

CF3

i

+

+

½80

CF3 47%

44%

9%

i, (CF3)2C
N2, hν

Figure 6.62

Trifluoromethylcarbene [95] also yields high proportions of insertion products in reactions with alkenes, whilst difluoromethylfluorocarbene is intermediate in reactivity because, although it undergoes a range of C2H insertion reactions, it is more selective than trifluoromethylcarbene [96].

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 159

Elimination Reactions

159

Polyfluoroalkylcarbenes have triplet ground states [89] and so reactions with alkenes give isomeric mixtures of cyclopropanes, as well as other side-products, in contrast to reactions involving difluorocarbene [80] (Figure 6.63). i H3C

CH3 i, (CF3)2C
N2, hν

F3C

CH3

F3C

CH3

F3C +

49%

CF3

H

H

H3C

CH3

cis 39%

½80

trans 8%

Figure 6.63

REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

C.H. DePuy and C.A. Bishop, J. Am. Chem. Soc., 1960, 82, 2535. H.F. Koch, D.B. Dahlberg, M.F. McEnfee and C.J. Klecha, J. Am. Chem. Soc., 1976, 98, 1060. N.B. Chapman and J.L. Levy, J. Chem. Soc., 1952, 1677. M. Hudlicky, J. Fluorine Chem., 1986, 32, 441. M. Hudlicky and T.E. Glass, J. Fluorine Chem., 1983, 23, 15. M. Hudlicky, J. Fluorine Chem., 1984, 25, 353. E. Baciocchi, R. Ruzziconi and G.V. Sebastiani, J. Org. Chem., 1982, 47, 3237. S. Alunni, V. Laureti, L. Ottavi and R. Ruzziconi, J. Org. Chem., 2003, 68, 718. H.F. Koch, D.J. McLennan, J.G. Koch, W. Tumas, B. Dobson and N.H. Koch, J. Am. Chem. Soc., 1983, 105, 1930. H.F. Koch in Comprehensive Carbanion Chemistry, ed. E. Buncel and T. Durst, Elsevier, Amsterdam, 1987. J. Hine, R. Wiesboeck and O.B. Ramsay, J. Am. Chem. Soc., 1961, 83, 1222. H.F. Koch and J.G. Koch in Carbanion Intermediates, ed. J.F. Liebman, A. Greenberg and W.R. Dolbier, VCH, New York, 1988. R.A. Bartsch and J.F. Bunnett, J. Am. Chem. Soc., 1968, 90, 408. P. Tarrant, A.M. Lovelace and M.R. Lilyquist, J. Am. Chem. Soc., 1955, 77, 2783. H.W. Davis and A.M. Whaley, J. Am. Chem. Soc., 1950, 72, 4637. R.P. Ruh, US Pat. 2 628 988 (1953); Chem. Abstr., 1954, 48, 1407b. P. Tarrant, R.W. Whitfield and R.H. Summerville, J. Fluorine Chem., 1971, 1, 31. R.D. Chambers, R.W. Fuss, R.C.H. Spink, M.P. Greenhall, A.M. Kenwright, A.S. Batsanov and J.A.K. Howard, J. Chem. Soc., Perkin Trans. 1, 2000, 1623. H. Matsuda, T. Hamatani, S. Matsubara and M. Schlosser, Tetrahedron, 1988, 44, 2865. W.H. Saunders and A.F. Cockerill, Mechanisms of Elimination Reactions, John Wiley and Sons, New York, 1973. D.J. McLennan, Tetrahedron, 1975, 31, 299. M. Hudlicky, Coll. Czech. Chem. Commun., 1991, 56, 1680. C.R.S. Briggs, D. O’Hagan, J.A.K. Howard and D.S. Yufit, J. Fluorine Chem., 2003, 119, 9. J.C. Tatlow, J. Fluorine Chem., 1995, 75, 7. R.P. Smith and J.C. Tatlow, J. Chem. Soc., 1957, 2505. D.E.M. Evans, W.J. Feast, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1963, 4828. J. Burdon, T.M. Hodgins, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1965, 2382. G. Fuller and J.C. Tatlow, J. Chem. Soc., 1961, 3198. D.J. Burton and Z.Y. Yang, Tetrahedron, 1992, 48, 189. P.G. Gassman and N.J. O’Reilly, J. Org. Chem., 1987, 52, 2481.

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31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71

Chapter 6

J.L. Adcock and H. Luo, J. Org. Chem., 1993, 58, 1999. S.F. Campbell, R. Stephens and J.C. Tatlow, Tetrahedron, 1965, 21, 2997. W.B. Hollyhead, R. Stephens, J.C. Tatlow and W.T. Westwood, Tetrahedron, 1969, 25, 1777. R. N. Haszeldine, Fluorocarbon Derivatives, Royal Institute of Chemistry, London, 1956. M. Yamabe and H. Miyake in Organofluorine Chemistry: Principles and Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum Press, New York, 1994, p. 403. N.T. Nakai, K. Tanaka and N. Ishikawa, Tetrahedron Lett., 1976, 17, 1263. J.M. Percy in Organofluorine Chemistry: Techniques and Synthons, ed. R.D. Chambers, Springer, Berlin, 1997, p. 131. H. Hata, T. Kobayashi, A. Amii, K. Uneyama and J.T. Welch, Tetrahedron Lett., 2002, 43, 6099. K. Uneyama and H. Amii, J. Fluorine Chem., 2002, 114, 127. D.J. Burton and J.L. Hahnfeld, Fluorine Chem. Rev., 1977, 8, 119. B.E. Smart in Chemistry of Organic Fluorine Compounds II, ed. M. Hudlicky and A.E. Pavlath, ACS, Washington DC, 1995, p. 767. J. Hine, Divalent Carbon, Ronald, New York, 1964. W.E. Parham and E.E. Schweizer, Org. Reactions, 1963, 13, 55. J. Hine and P.B. Langford, J. Am. Chem. Soc., 1957, 79, 5497. G.C. Robinson, Tetrahedron Lett., 1965, 1749. L. Anke, D. Reinhard and P. Weyerstahl, Liebigs Ann. Chem., 1981, 591. Y. Bessiere, D.N.H. Savary and M. Schlosser, Helv. Chem. Acta, 1977, 60, 1739. P. Balcerzak, M. Fedorynski and A. Jonczyk, J. Chem. Soc., Chem. Commun., 1991, 826. J. Hine and D.C. Duffey, J. Am. Chem. Soc., 1959, 81, 1129. J. Hine and D.C. Duffey, J. Am. Chem. Soc., 1959, 81, 1131. Y. Kobayashi, T. Taguchi, T. Morikawa, T. Takase and H. Takanishi J. Org. Chem., 1982, 47, 3232. T. Taguchi, T. Takigawa, Y. Tawara, T. Morikawa and Y. Kobayashi, Tetrahedron Lett., 1984, 25, 5689. T. Ando, H. Tamanaka, S. Terabe, A. Horike and W. Funasaka, Tetrahedron Lett., 1967, 1123. O.R. Pierce, E.T. McBee and G.F. Judd, J. Am. Chem. Soc., 1954, 76, 474. V. Franzen, Chem. Ber., 1962, 95, 1964. D.J. Seyferth, J. Organometal. Chem., 1973, 62, 33. S.F. Sellers, W.R. Dolbier, H. Koroniak and D.M. Al-Fekri, J. Org. Chem., 1984, 49, 1033. W.R. Dolbier, H. Wojtowicz and C.R. Burkholder, J. Org. Chem., 1990, 55, 5420. N.V. Kirii, S.V. Pazenok, Y.L. Yagupolskii, D. Naumann and W. Turra, Russ. J. Org. Chem., 2001, 37, 207. D.J. Burton and D.G. Naae, J. Org. Chem., 1973, 95, 8467. W.R. Dolbier and S.F. Sellers, J. Org. Chem., 1982, 47, 1. A. Greenberg and N. Yang, J. Org. Chem., 1990, 55, 372. Y. Bessard and M. Schlosser, Tetrahedron, 1991, 47, 7323. A.E. Feiring in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banke, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 339. R.E. Banks, J.M. Birchall, R.N. Haszeldine, J.M. Simm, H. Sutcliffe and J.H. Umfreville, Proc. Chem. Soc., 1962, 281. J.M. Birchall and R.N. Haszeldine, J. Chem. Soc., 1959, 3653. H. Millauer, W. Schwertfeger and G. Siegemund, Angew. Chem. Int. Ed. Engl., 1985, 24, 161. W. Mahler and P.R. Resnick, J. Fluorine Chem., 1973, 3, 451. P.B. Sargent and C.G. Krespan, J. Am. Chem. Soc., 1969, 91, 415. W.R. Dolbier, S.F. Sellers, B.H. Al-Sader, T. H. Fielder, S. Elsheimer and B.E. Smart, Isr. J. Chem., 1981, 21, 176. P.W.L. Bosbury, R. Fields, R.N. Haszeldine and G.R. Lomax, J. Chem. Soc., Perkin Trans. 1, 1982, 2203.

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72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96

161

W.P. Dailey, P. Ralli, D. Wasserman and D.M. Lemal, J. Org. Chem., 1989, 54, 5516. R.G. Cavell, R.C. Dobbie and W.J.R. Tyerman, Canad. J. Chem., 1967, 45, 2849. J.M. Birchall, R.N. Haszeldine and D.W. Roberts, J. Chem. Soc., Chem. Commun., 1967, 287. R.A. Mitsch, J. Am. Chem. Soc., 1965, 87, 758. V.M. Karpov, V.E. Platonov, I.P. Chuikov and G.G. Yakobson, J. Fluorine Chem., 1983, 22, 459. R.D. Chambers, R.P. Corbally, T.F. Holmes, and W.K.R. Musgrave, J. Chem. Soc., Perkin Trans. 1, 1974, 108. M. Rahman, M.L. McKee and P.P. Shevlin in Fluorine-Containing Molecules, ed. J.F. Liebman, A. Greenberg and W.R. Dolbier, VCH, New York, 1988. R. Sztyrbicka, M. Rhaman and M.E. D’Aunoy, J. Am. Chem. Soc., 1990, 112, 6712. D.M. Gale, W.J. Middleton and C.G. Krespan, J. Am. Chem. Soc., 1966, 88, 3617. J.H. Atherton and R. Fields, J. Chem. Soc. C, 1968, 2276. W.P. Dailey, Tetrahedron Lett., 1987, 28, 5801. D.M. Gale, J. Org. Chem., 1968, 33, 2536. R.N. Haszeldine and J.G. Speight, J. Chem. Soc., Chem. Commun., 1967, 995. D. Seyferth and G. J. Murphy, J. Organometal. Chem., 1973, 52, C1. J.P. Simons, J. Chem. Soc., 1965, 5406. R.A. Moss, Acc. Chem. Res., 1980, 13, 58. R.A. Seburg and R.J. McMahon, J. Org. Chem., 1993, 58, 979. D.A. Dixon, J. Phys. Chem., 1986, 90, 54. K.K. Irikura, W.A. Goddard and J.L. Beauchamp, J. Am. Chem. Soc., 1992, 114, 48. D. Seyferth and S.P. Hopper, J. Org. Chem., 1971, 26, 620. N.G. Rondan, K.N. Houk and R.A. Moss, J. Am. Chem. Soc., 1980, 102, 1770. B. Giese, W.B. Lee and J. Meister, Ann. Chem., 1980, 725. K.N. Houk, N.G. Rondan and J. Mareda, J. Am. Chem. Soc., 1984, 106, 4291. J.H. Atherton and R. Fields, J. Chem. Soc. C, 1967, 1450. R.N. Haszeldine, R. Rowland, J.G. Speight and A.E. Tipping, J. Chem. Soc., Perkin Trans. 1, 1980, 314.

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 162

Chapter 7

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

I PERFLUOROALKANES AND PERFLUOROCYCLOALKANES [1] A Structure and bonding [2, 3] 1 Carbon–fluorine bonds Carbon–fluorine bonds in the fluoromethane series shorten progressively upon increasing fluorination (Table 7.1), a feature that is not observed for other carbon–halogen bonds in halomethanes [2, 3]. Clearly, the carbon–fluorine bond shortening is accompanied by an increase in the bond energy of the carbon–fluorine bond, whilst the variation in bond lengths for the carbon–hydrogen bond is much smaller. In the chloromethanes the carbon– chlorine bond weakens slightly with increasing chlorine content. Table 7.1 Bond lengths r and bond strengths B of various halomethanes [3, 4] X¼F

CXH3 CX2 H2 CX3 H CX4

X ¼ Cl

˚) r(C2F) (A

B(C2F) (kJmol1 )

˚) r(C2Cl) (A

B(C2Cl) (kJmol1 )

1.385 1.357 1.332 1.319

459.8 500.0 533.5 546.0

1.781 1.772 1.758 1.767

354.0 335.1 324.7 305.8

Bond-shortening in fluoromethanes has been discussed by a number of authors. Pauling originally [5] introduced the concept of double-bond no-bond resonance (negative hyperconjugation, Chapter 4, Section IIIB) involving, in MO terms, interaction of non-bonding electron pairs of fluorine with a s
orbital of a carbon–fluorine bond, to account for the effect, and this is now well established [6] (Figure 7.1).

2 Carbon–carbon bonds The weakest bonds in perfluoroalkanes are the carbon–carbon bonds, so it is of interest as to whether the strengths of these bonds are affected by the introduction of fluorine. It is 162

Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 163

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives F F

C

F F

F

F

C

163

F F

F

F

C

F

etc.

½6

F

Figure 7.1

found that carbon–carbon bond strengths in a series of fluoroethanes increase upon a-fluorination (Table 7.2). Table 7.2 Carbon–carbon bond strengths and lengths in fluoroethanes [3] Ethane CH3 2CH3 CH3 2CH2 F CH3 2CHF2 CH3 2CF3 CF3 2CH2 F CF3 2CF3

˚) r(C2F) (A

BDE(C2C) (kJmol1 )

1.532 1.502 1.498 1.494 1.501 1.545

378.2 381.6 400.0 423.4 395.8 413.0

Paradoxically, the carbon–carbon bond in hexafluoroethane is stronger than in ethane, even though it is longer; as yet, such observations remain unaccounted for.

B

Physical properties

Since the molecular weight of a fluorocarbon is considerably higher than that of the corresponding hydrocarbon, we might expect boiling points to be increased. It can be seen from Figure 7.2 [7] that this is not so, and that there is a remarkable similarity between the boiling points of fluorocarbons and the corresponding hydrocarbons [8], the increase in molecular weight being offset by a decrease in intermolecular bonding forces in the fluorocarbon [9]. Perfluorocarbons have the potentially valuable property of dissolving useful amounts of certain gases, including oxygen, carbon dioxide and even fluorine, and the inertness of fluorocarbons to oxidation has led to a long-term study of fluorocarbon emulsions in water for use as ‘artificial’ blood and other transport applications [10]. Although working systems have been demonstrated, drawbacks associated with reactions of the immune system have, so far, limited their successful commercial development. Fluorinated fullerenes have been studied intensively [11].

C 1

Reactions Hydrolysis

Perfluorocarbons are essentially inert to hydrolysis unless heated to very high temperatures, although it has been calculated that the free energy of hydrolysis of carbon tetrafluoride is exothermic by 304 kJmol1 [12], and the inertness therefore stems from a high activation barrier. The carbon backbone in a perfluorocarbon is shielded towards attack by nucleophiles by the non-bonding electron pairs associated with the many adjacent fluorine atoms, and this is undoubtedly a major factor contributing to the relative inertness of fluorocarbons.

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 164

164

Chapter 7 150

100

Boiling point (
C)

50

0 4

2

6

8

Number of carbon atoms −50

−100

−150 Fluorocarbons Hydrocarbons

−200

Figure 7.2 Boiling points of alkanes

2 Defluorination and functionalisation [1] Either fusion with alkali metals or reaction with alkali-metal complexes with aromatic hydrocarbons will break down most fluorocarbon systems, due to the high electron affinities of these systems. Such reactions form the basis of some methods of elemental analysis [13], the fluorine being estimated as hydrogen fluoride after ion exchange. Surface defluorination of PTFE occurs with alkali metals and using other techniques [14]. Perfluorocycloalkanes give aromatic compounds by passage over hot iron and this provides a potential route to a variety of perfluoroaromatic systems (Chapter 9, Section IB). Electron transfer from other, less vigorous, reducing agents (Table 7.3) can result in selective defluorination, which arises from a single-electron transfer process, under very mild conditions (Figure 7.3). −

−

+e

CF2CF2

CF2CF2

n

−F n

CF2CF2

CF2CF

n-1

−

+e −

etc.

Figure 7.3

+e

−

CF2CF2

n-1

CF=CF

−F

CF2CF2

n-1

CF2CF

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 165

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

165

Table 7.3 Defluorination of perfluorocarbons Substrate

Reagents/Conditions

Product

F

F

Cp2 TiF2 Al, HgCl2 , THF, rt

F

F

F

F

Cp2 Co LiðO3 SCF3 Þ, Et2 O, rt

F

F

F

F

Ph2 C5O, Na THF, rt

F

F

Yield (%)

Ref.

40

[15]

53

[16]

62

[17]

When the reducing agent can also act as a nucleophile, such as thiolate anion [18] (Figure 7.4) or ammonia sensitised by mercury [19] (Figure 7.5), functionalisation of the unsaturated, fluorinated intermediate can occur.

SPh

SPh

PhS

SPh

PhS

SPh

i F

F

½18 −

SPh

+

i, PhS Na , DMEU, 70
C, 10 days

SPh

Figure 7.4

F3C CF F3C

NC

i

CF2 CF2CF3

NC

½19

CF2CF3

CN

CF3 HN

NH2

i F

F i, Hg/hν, NH3

Figure 7.5

NH2

½19

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 166

166

Chapter 7

3 Fragmentation Although perfluorocarbons are extremely thermally stable compounds, pyrolysis at elevated temperatures can lead to useful preparations of some simple alkenes [20] (Figure 7.6). F

725
C

CF2

C(CF3)2

+

70%

CF2

CFCF3

½20

20%

Figure 7.6

Vacuum pyrolysis of polytetrafluoroethene gives tetrafluoroethene as virtually the only product [21]; this unzipping reaction is almost unique amongst depolymerisation processes. At higher pressures the pyrolysis product contains other perfluorinated alkenes and perfluorocyclobutane, the proportions depending on the exact reaction conditions [22].

D Fluorous biphase techniques [1, 23, 24] The technique of using mixtures of perfluorocarbon and hydrocarbon solvents to aid separation and recovery of products, catalysts etc. was initiated by Horva´th and Rabai [25]. These mixtures of solvents may be largely immiscible at room temperature but will become miscible on heating, whereupon reaction will take place. On cooling, separation occurs and products may be recovered. If a component has an attached perfluoroalkyl group that is sufficiently long to render that component soluble in the perfluorocarbon (e.g. a catalyst), then recovery from the perfluorocarbon becomes easy [25] (Figure 7.7). In this example, the product aldehyde separates from the perfluorocarbon solvent [26]. However, because of the high cost of perfluorocarbons and their global warming potential, it seems unlikely that these approaches will be used in large-scale syntheses. CO/H2

CO/H2

1-octene 25
C, C7F14 [Rh] P(4-C6H4C6F13)3

Heat

1-octene 70
C, C7F14 [Rh] P(4-C6H4C6F13)3

CO/H2 n-nonanal 81% 25
C, C7F14

½26

[Rh] P(4-C6H4C6F13)3

Figure 7.7

Curran and co-workers have introduced a promising approach to separation and purification procedures by using fluorocarbon-coated solid phases for liquid-phase chromatography. This approach depends on attaching a variety of perfluorocarbon tags to functional compounds which render the eventual substrate mixture separable over the perfluorinated stationary phase [27, 28] (Figure 7.8).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 167

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives RF1

A1

A1

RF1

A6

6

B1

RF1

B6

RF6

167

½27, 28

i RF6

A6

RF

Separate Components

Mixture

Mixture

i, various chemical transformations Chromatography 1

RF

etc. = Fluorinated tag 1

6

B1

RF1

B6

RF6

Recovery of B -B and RF tags

Separate Components

Figure 7.8

II

PERFLUOROALKENES

A

Stability, structure and bonding

Substitution of hydrogen, in an alkene, by fluorine leads to increased reactivity for a number of processes; for example, with tetrafluoroethene, heats of addition of chlorine, hydrogenation and polymerisation are 58.5, 66.9 and 71:1 kJmol1 greater, respectively, than for the analogous reactions with ethene [3, 29]. These observations could be attributed either to an increase in the carbon–fluorine bond strength upon changing the hybridisation of the carbon atoms bonded to fluorine [30] or to p-bond destabilisation by fluorine [31]. Here it is reasonable to note the effect of fluorine and of perfluoroalkyl groups on orbital energies; in this regard, photoelectron spectroscopy is quite valuable. It is useful to emphasise, again, that electron-withdrawing groups lower orbital energies, and photoelectron spectroscopy confirms that perfluoroalkyl groups have this effect on attached p-bonds. The same technique [32, 33] also points to the ambiguous nature of a fluorine atom attached to a double bond (Chapter I, Section IIIB) where inductive electron withdrawal is offset by interaction of non-bonding electron pairs on fluorine with the p-system. Consequently, the effect of fluorine attached to a double bond on the energies of the p-orbitals is little different from that of hydrogen, whereas perfluoroalkyl is strongly stabilising. In contrast, a fluorine atom attached to a saturated site can only be a stabilising influence, so we can appreciate that there is a driving force towards decreasing the number of sites where a fluorine atom is attached to an unsaturated carbon centre. A consideration of the cyclobutene ring-opening reactions [34, 35] (Table 7.4) reveals that the changes in hybridisation of carbon bonded to fluorine are the same for both compounds T7.4A and T7.4B, and so any changes in carbon–fluorine bond energies must also be the same. Consequently, as DH for T.7.4A is more endothermic than for T7.4B,

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Chapter 7

Table 7.4 Substrate

Ring opening of cyclobutenes [34] Product

F2C

CF3

F2C

F

F2C

CF3

F CF3 T7.4B

F2C

Eað kJmol1 Þ

Keq at 3158 C

33.5

136.0

9000

48.9

197.0

5:6  103

1.7

192.5

8.4

F

F T7.4A

DHðkJmol1 Þ

CF3

this difference must be due to destabilisation of the p-system by fluorine, an effect which must increase with the number of fluorine atoms attached to the double bond. These conclusions are supported by the measurement of the p-bond dissociation energy [36] of CF2 5CF2 , which is 29 kJmol1 less than that for ethene. However, the situation is less clear for partly fluorinated systems such as CF2 5CH2 , in which the p-bond is 12:5 kJmol1 more stable than in ethene [37]. cis-1,2-Difluoroethene is more thermodynamically stable by about 48 kJmol1 than the trans isomer [38]. This observation, which has been termed the cis effect, appears to be a similar phenomenon to the conformational preference of 1,2-difluoroethane for the gauche form [39]. A number of explanations and theoretical calculations have been advanced [3, 39], with non-bonded attraction and conjugative destabilisation being the most widely discussed. Of course, it could be that fluorine atoms in the trans isomer of 1,2-difluoroethene have the more destabilising influence on the p-bond. All available data appear to point to the same underlying feature, that fluorine prefers not to be attached to unsaturated carbon; this most probably stems from repulsion between electron pairs on fluorine and those of the p-systems. Earlier discussions showed that similar repulsions are important in determining the stability of fluorocarbanions (see Chapter 4, Section VIIA), and that these repulsive forces appear to be critically interdependent with stereochemistry. Similar effects on fluoroalkenes are represented in Figure 7.9. The formation of a double bond involving sp2 -hybridised carbon, 7.9A, would lead to greater electron-pair repulsion than when formed from sp3 hybridised carbon (cf. 7.9A and 7.9B); the latter would lead to ‘bent bond’ formulation 7.9B. Extension of this approach leads to the conclusion that fluorine attached to a carbon– carbon triple bond would be considerably destabilising, since electron-pair repulsions with fluorine would then be at a maximum (Figure 7.10). This could partly account for the instability of fluoroalkynes, described later (Section IIIA, below). Of course, it must not

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

169

be forgotten that the electronegativity of carbon increases in the series sp3 , sp2 , sp and the carbon–fluorine bond strength decreases correspondingly.

2

3

7.9A, C sp

7.9B, C sp

F

109


109
90
F

F

C

109
C

Figure 7.9

F

C

C

Figure 7.10

B

Synthesis

There are four main general methods [40–42] for the preparation of perfluorinated alkenes, namely dehydrohalogenation, dehalogenation, pyrolysis and halogen exchange reactions of appropriate fluorinated precursors. The overall features of the mechanisms of each of these processes have already been discussed (Chapters 6 and 7, Sections I and II). Representative examples of each of these types of synthesis are collated in Table 7.5; clearly the method of choice for the synthesis of a particular fluoroalkene will depend

Table 7.5 Synthesis of perfluoroalkenes Reaction

Ref.

Dehydrohalogenation H F

KOH/H2O

F

[43, 44]

Reflux/30 min.

Contd

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170

Chapter 7

Table 7.5 Contd Reaction

Ref.

CF2CFHCF3

CF CFCF3

[45]

NaOH 85
C

F Cl

F

F KOH

[46]

F

H F

F

Dehalogenation Cl 200
C

CF2 CFCl

Zn, EtOH

F

F

[47]

100%

Cl

Pyrolysis i

CF2 CF2

CF2 CFCF3

[48]

i, 750-800
C, Atmos Press. i

(CF2 CF2)n

CF2 CFCF3

32%

CF2 C(CF3)2

+

CF2 CFC2F5

+

9%

[49]

53%

i, 700
C, Atmos Press. CF3CF2CF2CO2−Na+

∆

CF2 CFCF3

−CO2

[50]

Halogen exchange F3C

i

CCl2 CClCCl CCl2

H 59%

F

[51, 52]

CF3

i, KF, 200
C, NMP

Cl

i

F

72%

[51]

i, KF, NMP, 200
C

CCl2 CCl CCl CCl2

i

i, KF, 18-Crown-6, Perfluorocarbon

CF3C CCF3

[53]

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

171

upon the availability of suitable precursors. In this section we will confine ourselves to syntheses of per- and poly-fluoroalkenes, whilst other approaches to the preparation of selectively fluorinated alkenes will be discussed in other chapters. It is important to note that most of the simple highly fluorinated, commercially significant fluoroalkenes are synthesised from materials obtained by the Swarts reaction (Chapter 2, Section IIA) involving catalysed reactions of anhydrous hydrogen fluoride with chloroalkanes [54] (Figure 7.11) or bromoalkanes. HF catalyst

CHCl3

700
C

CHClF2

CF2

CF2

½54

Pt 860
C Vacuum CF2

CH3

HF

CCl3

catalyst

CH3

∆

CClF2

− HCl

CFCF3

CH2

CF2

Figure 7.11

Decarboxylation of fluoro-acids which, in turn, are prepared by electrochemical fluorination (ECF) on the industrial scale, is a useful route to longer-chain terminal fluoroalkenes [50] (Figure 7.12). E.C.F.

n-C3H7COF

−

+

n-C3F7COO Na

∆ −CO2

H2O

n-C3F7COF

C3F7

−F

n-C3F7COOH

½50

−

CF2=CFCF3

+

NaF

Figure 7.12

Perfluorocyclopentene is exceptional in being obtained from non-fluorinated materials by a simple one-step procedure, i.e. displacement of chlorine in perchlorocyclopentene by fluoride ion [51], although some polyfluorochloro- and polyfluorohydro-alkenes can be made by analogous processes [51, 52]. If a perfluorocarbon is used as the reaction medium with potassium fluoride/18-crown-6 complex, then a variety of products may be obtained, including hexafluoro-2-butyne [53]. Many useful, higher-molecular-weight fluoroalkenes can be conveniently prepared by fluoride-ion-induced oligomerisation reactions of smaller fluoroalkenes such as tetrafluoroethene and hexafluoropropene, and these methods are discussed in Section C.

C

Nucleophilic attack [55–57]

Fluoroalkenes are generally much more susceptible to attack by nucleophiles than by electrophiles and, in this respect, the chemistry of polyfluoroalkenes and their

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Chapter 7

corresponding alkenes may be said to be complementary [56]. Consequently, the term ‘mirror-image chemistry’ is appropriate to describe much of what follows (Figure 7.13). −

Nuc

F +

C C F

E

Nuc F

H +

H

H E

H

C

F C

C H

H+

Nuc

F

F

H C C

+

F

F

H

−

F

F

C

C

F

F

H

H

C

C

H

H

H

Nuc

E

C H

Nuc

Figure 7.13

Nucleophilic attack on a double bond proceeds via carbanionic intermediates; a consideration of the relative stabilities of such species as models for the corresponding transition states accounts for most, but not all, of the observations concerning nucleophilic addition to fluoroalkenes. The formation and direct observation by NMR of perfluoroalkyl anions in solution e.g. 7.14A, via addition of fluoride ion to perfluorinated alkenes [58] is analogous to the observation of carbocations by protonation of alkenes. The carbanions generated can be readily trapped by electrophiles [58]: in a classical experiment Wiley [59] showed that carbanions are intermediates in nucleophilic addition to tetrafluoroethene, by trapping the intermediate with dimethylcarbonate. Later developments showed that various nucleophiles may be used, and that fluoro-esters may be employed as the trapping agent [60, 61] (Figure 7.14).

1 Orientation of addition and relative reactivities Problems of orientation of attack and reactivities of fluorinated alkenes arise in a way that is analogous but entirely complementary to the classical problems of electrophilic attack on alkenes. For example, typical of the results that we must be able to account for is the reaction of methoxide in methanol which occurs specifically at the CF2 5 site in perfluoropropene (Figure 7.15). Also, there is a very wide range of reactivity with perfluoroalkenes: for example, reactions of tetrafluoroethene usually require base catalysis, whereas perfluoroisobutene reacts with neutral methanol. (Caution: Like all alkylating agents, fluorinated alkenes should be treated as being potentially toxic [62, 63]. For example, perfluoroisobutene is an extreme case and should be avoided.)

2 Reactivity and regiochemistry of nucleophilic attack A great deal of chemistry involving nucleophilic attack on fluorinated alkenes may be rationalised on the basis of some simple ground rules and assumptions: (1)

There is a significant ion–dipole interaction [64] that contributes to the much greater reactivity of alkenes bearing fluorine rather than chlorine at comparable sites [65], and a terminal difluoromethylene is especially reactive [66] (Figure 7.16).

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives F3C

CF2CF3

tetraglyme +

F3C

F3C

rt

F

½58

+

Cs

CF2CF2CF3

CsF

173

F3C 7.14A, Observable by NMR

I

CF3 CF2CF2CF3 CF3 −

CH3O

+

CF2

−

CF2

½59

CH3OCF2CF2

(CH3O)2C=O CH3OCF2CF2CO2CH3

74%

O Nuc

CF2 CF2

NucCF 2CF2 i,

eg

−

−

−

−

RFCOOR

i

NucCF2CF2 C RF

½60, 61

OR

−

Nuc = N3 , PhO, CH3O, CH3S.

Figure 7.14 −

CH3O

CF2

CFCF3

CH3OCF2CFCF3

CH3OH

CH3OCF(CF3)CF2

CH3OCF2CFHCF3

−

CH3O

Figure 7.15

(2)

(3)

Fluorine attached to carbon, which is itself adjacent to the carbanionic site (7.16A), is carbanion-stabilising and therefore strongly activating, for example when X or Y in 7.16A is CF3 . When fluorine is directly attached to the carbanionic site, e.g. X or Y ¼ F in 7.16A, the result is usually activating, but much less so than in (2). Thus, we have an increase in reactivity in the series 7.17A–7.17C [67–69], and we can see that this corresponds to an increase in stabilities of the derived intermediate carbanions 7.17D–7.17F (Figure 7.17).

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174

Chapter 7 δ C

F

Nuc

C δ

F δ

δ

δ F

>>

CXY

δ Cl

C

Nuc

etc.

CXY

CF2 7.16A

Figure 7.16

CF2

CF2

<

CF2

7.17A

<

CFCF3

CF2

7.17B

−

NucCF2CF2

7.17C

NucCF2CFCF3

<

<

NucCF2C(CF3)2

7.17E

7.17D

C(CF3)2

7.17F

Figure 7.17

Furthermore, the rates of nucleophilic addition of diethylamine have been found to increase in the series CF2 5CF2 < CF2 5CFCl < CF2 5CFBr [70] (Figure 7.18), again in the order of increasing stability of the supposed intermediate carbanion. (C2H5)2NH

CF2

CFBr

−H

+

+

+H

−

(C2H5)2NCF2CFBr

(C2H5)2NCF2CFBrH

Figure 7.18

The order of reactivity CF2 5CðRF Þ2 > CFRF 5CðRF Þ2 > ðRF Þ2 C5CðRF Þ2 (where RF ¼ perfluoroalkyl) has been clearly established from the isomeric system, 7.19A–7.19C, in competition for reactions with methanol [68] (Figure 7.19). −

F CF2

C(RF)CF2CF3 7.19A

CF3CF2(CF3)C

C(CF3)CF2CF3

½68

7.19B −

F

RF = CF3CFCF2CF3 CF3CF

C(CF3)RF

7.19C

Figure 7.19

Intermediate carbanions formed by the addition of nucleophiles to fluorinated alkenes may also be intercepted via halophilic processes [71] (Figure 7.20), as well as trapping by electrophiles (see Figure 7.14).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 175

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives −

CF2

CH3O

CFBr

½71

CH3OCF2CFBr

CF2

175

CFBr

CH3OCF2CFBr2

CF2

CF

Other products

Figure 7.20

However, the type of argument outlined above is insufficient to account for the reactivity of perfluoropropene being greater than that of perfluoro-2-butene (7.21A) (Figure 7.21), because the corresponding intermediate (7.21B) could only have marginally different stability from the intermediate derived from perfluoropropene (7.17E). There is also the greater reactivity of 7.22A than 7.22B to account for, where any difference in stability of intermediate carbanions 7.22C and 7.22D would also be marginal (Figure 7.22). −

Nuc

CF3CF

CFCF3

NucCF(CF3)CF(CF3)

7.21A

Products

7.21B

Figure 7.21 RFCF C(RF)2 7.22A NucCF(RF)C(RF)2 7.22C

>

(RF)2C C(RF)2 7.22B

RF = Perfluoroalkyl

NucC(RF)2C(RF)2 7.22D

Figure 7.22

Consequently, a frontier-orbital approach has also been used to account for reactivity and orientation of attack [72]. This approach recognises that HOMO–LUMO interaction, between nucleophile and fluorinated alkene respectively, will be important, and that replacing a fluorine atom that is directly attached to unsaturated carbon in a fluorinated alkene by trifluoromethyl reduces LUMO energy. This increased HOMO–LUMO interaction correspondingly increases reactivity, providing that the trifluoromethyl groups are on the same carbon atom of the double bond, i.e. as in 7.17A–7.17C. However, coefficients also appear to be important, and introduction of trifluoromethyl increases the coefficient in the LUMO at the adjacent carbon, i.e. as shown for 7.23A (Figure 7.23). When two trifluoromethyl groups are attached to adjacent carbon atoms (7.23B), then it is reasonable to assume that their effect on coefficients, and hence on reactivity, is opposing; consequently the reactivity order CF2 5CF2 < CF2 5CFCF3 > CF3 CF5CFCF3 is observed.

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176

Chapter 7 F3C

F3C C

C

CF3 C

C

F3C 7.23A

7.23B

Figure 7.23

Strain is a very important factor affecting reactivity. This is probably best illustrated by the relative reactivities of the dienes 7.24A–7.24C (Figure 7.24) [73] towards methanol, giving the methoxy derivatives indicated. Diene 7.24A reacts vigorously with neutral methanol, diene 7.24B reacts only over several days, while base is required to induce reaction with diene 7.24C. Electronic effects in the dienes 7.24A–7.24C are essentially equivalent and, therefore, these considerable differences in reactivity may be taken, generally, as illustrative of the contributions that angle strain may introduce. X

X

X F

F Y

X, Y = F (7.24A) X = F, Y = OMe

F

F

CF3 CF3

F3C F3C

Y

Y X, Y = F (7.24B) X = F, Y = OMe X = Y = OMe

X, Y = F (7.24C) X = F, Y = OMe X = Y = OMe

Figure 7.24

3 Products formed The nature of the products formed in these processes may be regarded as being dependent upon the fate of an intermediate carbanion (7.25A in Figure 7.25): this can lead to proton abstraction from the solvent to give 7.25B; elimination of fluoride to give 7.25C; or, if the opportunity is available, an SN 20 process, e.g. by elimination of fluoride ion accompanied by allylic rearrangement to give 7.25D. The ratio of elimination to addition increases with the reactivity of the alkene, because the stability of the carbanion 7.25A increases and, at the same time, 7.25A becomes correspondingly less basic. Of course, the amount of alkene 7.25C also depends on whether the reaction is simply a base-catalysed process or whether a molecular equivalent of base is present. These processes are illustrated in Figure 7.26 [74, 75]. All three types of product are seen in many reactions between fluoroalkenes and nucleophiles [55, 76] (Figure 7.27). With very strong nucleophiles, polysubstitution may occur [77] (Figure 7.28). With ammonia and other nitrogen bases, a variety of unsaturated compounds may be obtained, such as nitriles and triazines [78–80] (Figure 7.29).

4 Substitution with rearrangement – SN20 processes Examples of substitutions that are accompanied by migration of the double bond are very common with fluoroalkenes; although in most cases it is not established whether these

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

Nuc

C

C

F

R

Nuc-H Nuc

−

C

C

H + Nuc

F

R

(Base catalysed addition)

7.25A

7.25B

177

−

−F

SN2' R = −CFR'2 Nuc

Nuc

R' F

R

R' 7.25D

7.25C

Figure 7.25 C4H9O− Na+ n-C4H9OH

+

CF2

CF2

0-40
C

n-C4H9OCF2CF2H

81%

½74

CH3OCF2CH(CF3)2

65%

½75

Room CH3OH

CF2

C(CF3)2

Temp.

CH3OCF

C(CF3)2

8%

Figure 7.26 i CF2

CH3OCF2CFHCF2C4F9

(45%, addition)

+ CH3OCF

(15%, substitution)

CFCF2C4F9

CFCF2C4F9

+ CH3OCF2CF

CFC4F9

½76

(40%, SN2')

i, CH3O− Na+, CH3OH, 50
C

Figure 7.27

4C6H5Li + CF2 CF2

Room Temp

(C6H5)2C C(C6H5)2

½77

Figure 7.28

reactions are concerted, they will be referred to as SN 20 processes here [81] (Figure 7.30). That substitution occurs by attack at the CF2 5 group, rather than direct displacement of chloride from 2CF2 Cl, has been deduced from the fact that, under equivalent conditions, C6 H5 CClF2 , CClF5CF2CClF2 and CCl2 5CCl2CClF2 are unreactive [82]. In non-aqueous media the relative order of reactivity of the attacking halide ions, as nucleophiles in these processes, is F > Cl  I [83]. This in itself indicates that the

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178

Chapter 7 XHFC CF2

NH3

CFX

CFHX

N C

C

N

N

½78

C CFHX

CF3CF

(CF3)2C

CF2

CF2

Vap.

NH3

Et2O

NH3

½79

CF3CHFCN

Phase

(CF3)2CHFCN

−60
C

½80

21%

(CF3)2CHCONH2

13%

Figure 7.29 CH3O−

CF2

CFCF2Cl

CH3OCF2CF

CF2

Cl−

½81

Figure 7.30

C6H5

CF2 + C2H5O−

k1

C6H5 CCF2OC2H5

R

products

½84

R

R

k1 x 103s−1 (77
C)

CF3

1.9

CF2Cl

1.8

CF2CF3

0.67

Figure 7.31

bond-making process is most important and that the reactions involve a two-step addition–elimination, rather than a concerted displacement in which the most polarisable anion would be the most reactive. The same conclusion was drawn from a comparison of the rates of reaction of various alkenes with ethoxide in ethanol under pseudo first-order conditions [84] (Figure 7.31). Rearrangement products were only obtained when R was CF2 Cl, where elimination of chloride was easier, but the rate constants for the other two examples are comparable, which indicates a rate-controlling addition step (k1 ). In general it is very difficult to make any distinction between a concerted process and the involvement of a short-lived carbanion. For clarity a number of alkene rearrangements in the following text are written as two-step processes, but it should be emphasised that they could involve concerted mechanisms. Products arising from substitution with rearrangement are frequently encountered in reactions of cyclic fluoroalkenes and in fluoride-ion-induced rearrangements (Subsection 6, below).

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

179

The literature concerning reactions between nucleophiles and fluoroalkenes is now extensive and is included in various reviews [41, 55, 57, 85–92] and books devoted to organofluorine chemistry (see the relevant chapters in the general textbooks listed in Chapter 1, Section I). Some examples of reactions between fluoroalkenes and an illustrative selection of nucleophiles are recorded in Table 7.6. The many unusual products and the wide scope of these reactions will be apparent even from such a brief overview of the subject. Examples of reactions involving bifunctional nucleophiles are also included, whereas reactions involving initial attack by fluoride ion as the nucleophile are discussed in Subsection 6, below.

Table 7.6 Reactions of fluoroalkenes with nucleophiles Reaction

Ref.

Carbon nucleophiles C8F17 +

C8F17SiMe3

F

F

i

CF2 CF2

NCCF2CF2CO2CH3

95%

[93]

[60]

72%

i, NaCN, CO2, (CH3O)2SO2 i

XYCCF2

Ph2CCN

Ph2C(CN)CF2CXY

[94]

i, Phase Transfer Conditions Ph2C(CN)CF=CXY

Ph2C(CN)CF2CHXY i

Ph-CF CFCF3

Ph2C CFCF3

PhCF C(CF3)Ph

[95] i, PhLi, Et2O Ph2C C(CF3)Ph (1 : 3.3 : 2.1) NMe2

NMe2

[96] +

F

F

CH3CN, rt 73% F

CH3MgX

CF2 CCl2

CH3CF2CCl2H

F

[97]

CH3CF CCl2

Contd

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180

Chapter 7

Table 7.6 Contd Reaction

Ref.

Nitrogen nucleophiles F F N

rt

+ CH3NH2

CF CF2

F

F

[98]

N N

H

CH3

78%

F

CF3

C2F5

F

C2F5

C2F5

NH3, Et2O 0
C

F

CH2CN

F3C

[99]

94%

C2F5

C2F5

F3C

Oxygen nucleophiles F3C

CF3

O

F3C

CF3

CF3

+ C2F5

C2F5

C2F5

O

F3C

i

C2F5

[100] H

C2F5 28%

62% i, NaOCl, H2O, CH3CN F3C

xylene

CF2 + Bu3SnOMe

F

OMe

[101]

H

i O

Ph F

F3C H

OH

H

F 62%

0
C

F3C

F3C

78%

[102]

68%

[103]

Ph

F i, Montmorillonite (cat), KIO3, Hexane, Reflux O i

(CH2OH)2

C(CF3)2

CF2 C(CF3)2 i, CH3CN, −5 to 0
C

O

Phosphorous nucleophiles C3F7CF CF2 + Bu3P

C3F7CF CFP(F) Bu3

[104]

(100%, Z)

Contd

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181

Table 7.6 Contd Reaction

Bu3P

Ref. i

CF2 CFCF3

Bu3P CF CFCF3

[105]

F

i, Et2O, −70
C to rt

BF3.Et2O CF3

F I

ii

Bu3P CF CFCF3

−

BF4

F ii, I2, DMF, NaCO3

F

+ Ph3P

F

[106] PPh3

Sulphur nucleophiles F3C

F

F3C

S

F3C

K2S, DMF

F3C

F i

CF3

[107]

CF3

S

29%

CF3CFHCF2SC( S)NMe2

CF2 CFCF3

62%

+ CF3CF CFSC( S)NMe2

63%

[108]

i, Me2N CS2− Na+, DMA, 20
C

Halide ions I NaI, DMF

F

[109]

F

Transition metal nucleophiles F

F

−

+ Re(CO)5

[110] Re(CO)5

Reduction PhCF CFCF3

i

F

CF3 9%

Ph

H

[111]

i, LiAlH4, glyme, 70
C

Contd

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182

Chapter 7

Table 7.6 Contd Reaction

Ref.

Bifunctional nucleophiles CF3 C2F5

HO +

CF3

F3C

i

C2F5

F3C C2F5

CF3

OH i, Na2CO3, tetraglyme

58%

i CF3CF CFCF3 +

77%

I

N

[113]

N

NH2

CF3

N i, K2CO3, CH2Cl2, rt

CF3

OH +

O i, ii F

[114]

F

NH2

N

i, K2CO3, CH3CN ii, NEt3

59%

i Li

[112]

O

O

CF CF

Li

n i, CF2 CF2, Et2O, −110
C SH

[115]

n = 10−20

S i

CF2 CFCF3

CH(CF3)2

NH2

[116]

N i, THF, i-Pr2NEt i

Me3SiOCH2(CF2)3CH2OSiMe3

F

[117]

OCH2(CF2)3CH2O

i, CsF, Glyme, Stepwise F

F OCH2(CF2)3CH2O

Contd

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

183

Table 7.6 Contd Reaction

Ref. N

i D.B.U. + CF3CH CFCF3

[118]

N F3C

CF2H

i, Hexane, rt

D. B. U., 1, 5-diazabicyclo [3.4.D] nonene-5

5

Cycloalkenes

The various reactions of cyclic polyfluoroalkenes [85] (Figure 7.32) can largely be explained on a similar basis to that described above, although the opportunity for some rather more subtle orientation effects arises. Vinylic fluorine is generally replaced in preference to other vinylic halogens, either in the same molecule or in comparable systems, e.g. in the reaction of 7.32A with a deficiency of alkoxide ion. In these cases, vinylic substitution is usually preferred over SN 20 processes. Cl F F

C2H5O−

Cl

½85

F OC2H5

7.32A

Figure 7.32

With equivalent halogen atoms at the vinylic positions, the remaining substituents have a significant effect on the orientation of nucleophilic attack [85] (Figure 7.33). Attack on 7.33A occurs to give predominantly 7.33C and 7.33D; this has been interpreted as indicating that CCl2 adjacent to the intermediate carbanion is more stabilising than CF2 , and similar deductions concerning CF2 and CH2 could be made from the exclusive formation of 7.34B from 7.34A (Figure 7.34). It has been suggested that an additional factor to be considered in determining the products from polyfluorocyclohexenes is the stereochemistry of the elimination step [119] (Figure 7.35). Elimination of fluoride ion may occur from the carbanion 7.35B, produced by reaction of 7.35A with methoxide ion, by an outward (displacement with rearrangement) or inward (vinylic displacement) process. In order to account for the results shown, it was suggested that anti addition of methoxide occurs and that the carbanion 7.35B partially retains its configuration [119]. Then competition occurs between an electronically favoured syn inward elimination of fluoride from 2CFOCH3 , and the stereochemically favoured anti outward elimination of fluorine from 2CF2 [120] (Figure 7.36).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 184

184

Chapter 7 F

F

Cl

F F

Cl

F

C2H5OH

Cl

KOH

Cl

OEt Cl

Cl OEt

Cl

Cl

Cl

Cl

Cl

F

7.33B, 10% F

7.33A

OEt

F

Cl

Cl Cl

Cl

F

Cl

F

OEt +

OEt

Cl

Cl

Cl

Cl

Cl

F F

7.33C, 61%

7.33D, 23%

Figure 7.33

F

F

F

F

−

F

F

F

C2H5O

F

F OEt

F

OEt

F

7.34A

7.34B

Figure 7.34 F R

R MeO−

F

R F

F

F

F

7.35B

F OMe

7.35C

7.35D

R

%

%

H

49

51

CH3

54

46

OCH3

38

62

Figure 7.35

½119

F

OMe

OMe

7.35A

R +

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives F

F

F F

F

F

F

R

F

F MeO F

F

F

F F

185

F

F F

R

F

MeO

7.35B

Figure 7.36

6

Fluoride-ion-induced reactions [56, 57, 121]

In the preceding sections we outlined reactions of fluoroalkenes with many types of nucleophilic species, but reactions involving initial attack on fluoroalkenes by fluoride ion have been reserved for a separate discussion here. Pioneering work by Miller and co-workers [55, 83] established that carbanions can be generated by reaction of fluoride ion with fluoroalkenes and an important analogy was drawn between the role of fluoride ion in reactions with unsaturated fluorocarbons, and the proton in reactions with unsaturated hydrocarbons [83]. In spite of the obvious misgivings in trying to draw an analogy between carbanion and carbocation processes, the model has been taken a surprisingly long way [56] (Figure 7.37). Addition F

−

F +

+

C

C

F3C

C

C

C

H3C

C

E

F3C

C

E

F3C

C

Nuc

F Compare

H

+

H +

−

Nuc

H

Substitution with Rearrangement F F −

F

F

F

F F F

−

+

F

F

Compare H +

H

H

H

Figure 7.37

H H H

+

+

H

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186

Chapter 7

7 Addition reactions Addition of an alkali-metal fluoride, frequently KF, CsF, ðMe2 NÞ3 Sþ Me3 SiF 2 (soluble in organic solvents) or a tetraalkylammonium salt, to a fluoroalkene in an aprotic dipolar solvent is usually the method used to generate perfluorocarbanions. Some of these intermediates have been directly observed by NMR [58, 121]. The intermediate carbanions may be trapped by a variety of electrophiles, and some examples are given in Table 7.7. Table 7.7 Fluoride-ion-induced addition reactions to fluoroalkenes Reaction

Ref.

F3C

CF2-CF3

F3C

F

CF3 CsF

+ CH3I

C3F7

C

DMF

CH3

79%

[122]

CF3 O

KF, DMF

CF2 CFCF3 + PhCOCl

CF3

Ph CF3 −

KF CF2 CF2

CH3CN

i, ii

CF3CF2

66%

[123]

F

CF3CF2CO2H

75%

[124]

i, CO2, 150
C, ii, H2SO4

−

+

CF2 CFCF3 + C6H5N2 Cl

F3C F F3C

CsF CH3CN

N N C6H5

[125]

41% CF3 CF2 C(CF3)2

+ C6H5SCl

CsF

F3C

glyme

C

SC6H5

82%

[126]

CF3

CF2 CFCF3 + S

KF, 120
C

F3C F3C

CF3

S

70%

[127]

CF3

S Br

F

F

CsF, Br2

CF2 CFCF3 + IF5 + I2

F

150
C

[128]

F

(CF3)2CFI

99%

[129] Contd

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

187

Table 7.7 Contd Reaction

Ref. CF3

CF3

F3C

+ KF F3C

+

I2

200
C

IF5

+

CF3CF2

F

C

I

79%

[130]

CF3 i

Hg(CF(CF3)2)2

2CF2 CFCF3 + HgCl2

[131]

i, KF, (CH2OMe)2, 50
C i

(CF3)2CFSO2F

CF2 CFCF3 + SO2F2

[132]

i, KF, CH3CN, 150
C, Autoclave F i

E C C E +

F

E = CO2CH3

F

E

E

[133]

i, CsF, tetraglyme

The related reactions of polyfluorinated carbanions with fluoroarenes (Figure 7.38) will be discussed fully in Chapter 9, Section IIB. CF(CF3)2 −

F

F N +

CF2

CFCF3

(CF3)2CF

F

½134

N

Figure 7.38

8

Fluoride-ion-catalysed rearrangements of fluoroalkenes

In the absence of electrophiles, loss of fluoride ion from intermediate carbanions may occur in a manner such as to yield the most thermodynamically stable fluoroalkene, often resulting in isomerisation of the original reactant. Fluoroalkenes with the fewest fluorine atoms attached to the double bond are generally the most thermodynamically stable (see Section IIA above). Consequently, ‘internal’ isomers are usually to be expected as the result of fluoride-ion-induced processes such as those indicated in Figure 7.39 [135, 136]. A number of remarkable fluoride-ion-induced rearrangements have been documented; one example is given in Figure 7.40. The possibility that many of these rearrangements are addition–elimination reactions rather than concerted SN 20 processes is supported by the isolation, in some cases, of

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188

Chapter 7 C3F7CF2CF

CsF

CF2

CF3 F

C3F7CF

diglyme

F3C

KF, MeCN CF

CFCF3

18-crown-6

½136

CF2CF3

F3C

CF3

½135

95%

CFCF3

96%

F

Figure 7.39

CF2 F

F

F2C

F

½137

F

F2C F

F

−

−

F

F

F

CF2 F2C

F

F2C CF2 F F F CF2 F

i, ii

F

F2C

F

F2C CF2 F

F −

i, −F ;

ii, Rearrangement

Figure 7.40

cyclised products, resulting from internal nucleophilic attack by an intermediate carbanion [138] (Figure 7.41). In many thermally induced rearrangements, it is often difficult or impossible to distinguish between a thermally induced fluorine-atom shift and the type of fluoride-induced rearrangement that we have just exemplified. However, evidence for photochemically induced 1,3-shifts of fluorine in the equilibrium between 7.42A and 7.42B is very convincing [139] (Figure 7.42).

9 Fluoride-ion-induced oligomerisation reactions Since fluoroalkenes are so susceptible to nucleophilic attack, we might have expected anionic polymerisation, initiated by fluoride ion, to occur readily. As we have noted, fluorocarbanions are readily generated by fluoride-ion attack on fluoroalkenes; these

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives −

F

CF

F2C +

CF2

CFCF2CF

189

CF2

CF2

½138

CF CF3

F

F

F3C

F3C

Figure 7.41 CF2 hν F

F

F

F

F

F

½139

7.42A hν F

(Photoequilibrium)

95%

F 7.42B

Figure 7.42

carbanions do indeed react further with the original fluoroalkenes but this results in only short-chain oligomers [56, 57, 92] rather than polymers. This occurs because the extending carbanion loses fluoride ion (Route A, Figure 7.43), rather than continuing the propagation step (Route B, Figure 7.43). n −

F

F

+

½56, 57, 92

F etc.

n+1

B, Propagation

−

A, Elimination of F

F

Fluoroalkenes n+2

Figure 7.43

By contrast, anionic polymerisation of hexafluoro-2-butyne (see Section IIB) proceeds rapidly because elimination of fluoride ion from the propagating anion is difficult, in that it would require the formation of allenes. The oligomerisation of tetrafluoroethene [91, 92, 140–142] demonstrates how processes like this can be used to build up useful, synthetically more sophisticated systems from readily available fluoroalkene precursors (Figure 7.44). The product distribution

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190

Chapter 7 −

CF2

F CF2

CF2

CF2 CF3CF2CF2CF2

CF3CF2 A

−

−F

CF3CF2CF

½91, 92, 14042

CF2 −

+F CF3CF2 CF3

−

C

CF3 CF3

C

−

F

SN2'

CF3 A

C

CFCF3 B

CF2 −

F

CF3

CF3

C2F5 F C2F5

−

A

B

CF3

CF3CF

C2F5

F

F, Dimerisation

CF3

C2F5

C2F5

CF3 Tetramer

Pentamer

Figure 7.44

depends upon the reaction conditions, with higher pressures generally leading to greater proportions of higher-molecular-weight products [140, 143]. Similar fluoride-ion-induced oligomerisations of hexafluoropropene [143, 144] (in which only dimers and trimers are formed, due to increased steric hindrance in the propagation step) and chlorotrifluoroethene [145] have been described. In each of these cases, highly branched fluoroalkene systems are formed, due to the tendency of the intermediate carbanion to lose fluoride ion, giving the most thermodynamically stable fluoroalkene. ‘Mixed’ oligomers can also be produced by fluoride-ion-initiated reaction between two different fluoroalkenes [146] (Figure 7.45), in which initial fluoride-ion attack occurs on the most reactive fluoroalkene (section IIC, Subsection 2). Oligomerisation of fluoroalkenes can also be initiated by tertiary amines, such as pyridine [147], trimethylamine [148] and tetrakis(dimethylamino)ethylene [149], via processes that involve either initial ylid formation or the generation in situ of an active source of fluoride ion.

10 Perfluorocycloalkenes Perfluorocyclobutene is much more reactive than perfluoro-cyclopentene or -cyclohexene and this enhanced reactivity is obviously attributable to relief of angle strain on carbanion formation. Perfluorocyclobutene [147, 150] gives a trimer and an equimolar mixture of

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives −

(CF3)2C

CF2

−

+F

CF2

(CF3)3C

CF2

− (CF3)3CCF2C F2

½146

(CF3)2C

−

(CF3)3CCF2CF2CF

−F

C(CF3)2

191

CF2

−

(CF3)3CCF2CF2CF2C(CF3)2

60%

Figure 7.45

dimers (see the preceding section) whilst perfluorocyclo-pentene and -hexene give dimers only [151] (Figure 7.46). −

F

F

A

F

F

A

F

½151

−

−F −

−

F

F

F

F

F

F

F

F

A

F F F

Figure 7.46

For the resultant fluorocycloalkene dimers [56, 147], the number of fluorine atoms at the double bond is not the controlling factor in determining the position of equilibrium. In Figure 7.47, only 7.47A1 is observed from perfluorocyclohexene, preserving one strainfree ring, whereas 7.47B2 is formed exclusively from perfluorocyclopentene, thereby minimising eclipsing interactions. In contrast, equivalent proportions of 7.47C1 and 7.47C2 are formed from perfluorocyclobutene as a result of the reduced angle strain in 7.47C1 over 7.47C2, which compensates for eclipsing interactions.

D

Electrophilic attack [152]

In general terms, highly fluorinated alkenes are relatively resistant to attack by the types of reactant that are normally considered to be electrophilic in character [55, 153–155]. When one or more perfluoroalkyl groups are attached to the double bond, then the system

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192

Chapter 7 −

F F

F

F

F

½56, 147 (Not observed)

7.47A1

7.47A2 F

F

F

F

F

(Formed exclusively) 7.47B1

7.47B2 −

F F

F

F

F

(Equimolar mixture) 7.47C1

7.47C2

Figure 7.47

becomes particularly resistant to electrophilic attack, although hydrofluoroalkenes and chlorofluoroalkenes will react with quite a range of electrophilic reagents. These effects correspond to the expected influence of these groups on carbocation stability. Many reactions are known [55, 154, 155] that involve addition of, for example, halogens, interhalogen compounds, hydrogen halides and haloalkanes, sometimes in the presence of Lewis acids, to fluoroalkenes; it is quite probable that many of these involve electrophilic attack, although other possibilities often arise. A number of reactions using anhydrous hydrogen fluoride as solvent have been formulated as involving electrophilic addition of Xþ F . Hexafluoropropene is unreactive towards anhydrous hydrogen fluoride, even at 2008 C, but silver fluoride in anhydrous hydrogen fluoride reacts at 1258 C and it has been suggested, therefore, that an initial electrophilic addition of silver fluoride occurs [156] (Figure 7.48). AgF

CF2

CFCF3

HF

½156

AgCF(CF3)2

125
C HF

HCF(CF3)2

AgF

Figure 7.48

Mercuric fluoride under similar conditions gives a stable mercurial and it was suggested that strong solvation of fluoride ion, to give Hn F nþ1 , inhibits nucleophilic attack by this fluoride ion but promotes dissociation of metal fluorides, therefore leading to attack by metal cations [156] (Figure 7.49).

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives −

+

HgF2

nHF

HgF2

2CF2 CFCF3

HnF

HgF

HF 85
C

Hg[CF(CF3)2]2

n+1

etc

193

½156

60%

Figure 7.49

A variety of interesting electrophilic addition processes have been developed, where additions (where the electrophile is, for example, Cl, Br, I, NO2 , 2OCH2 2, CH2 NH2 , CH2 OH etc.) to fluoroalkenes are achieved by reaction with a series of reagents (Table 7.8). Table 7.8 Electrophilic additions to fluoroalkenes Reaction

Ref. BF3

CF2 CCl2 + HF

[157]

CF3CHCl2 + polymer H AlCl3

C10H21CH CF2 + C2H5COCl

C10H21

CO.C2H5

C

[158]

CF2Cl C6H5 CF3

CF3

C6H5

+ Br2 F

Br

F

C

C

F

F

Br

86%

[159]

anti : syn 1:1

CF2 CH2

+ HI

−20
C

HNO3

CF2 CF2

CH3-F2I + polymer

i

CF3CF2NO2

[160]

93%

[161]

i, HF, 20
C

CF2 CFCF3

HNO3

i

(CF3)2CFNO2

76%

[154]

i, HF, 60
C

FClC CFCl

HNO3

i

NO2CFClCOOH

63%

[162] i, H2SO4, rt i H2C CHF + CH3COCl

CH3COCH2CHFCl

70%

[163]

i, FeCl3, CH2Cl2, 0
C

Contd

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194

Chapter 7

Table 7.8 Contd Reaction

Ref.

CF2 CFCF3 + IF5/I2 CF2 CF2 + IF5/I2 CF2 CXCF3 + BF3/ICl/HF

(CF3)2CFI

99%

[129]

CF3CF2I

86%

[129]

60-80%

(CF3)2CXI

[164]

X = H, F

i

CF2 CFCl + (CF3)2CO

F3C

[165, 166]

F

i, AlClXFY, 100
C

98%

O

F3C Cl

F

F

i CF2 CFCF3 + CH2F2

FCH2CF(CF3)2

90%

[167] i, SbF5, 35−50
C

The orientations of addition (Table 7.8) are consistent with an electrophilic process (Figure 7.50), bearing in mind that fluorine attached to positively charged carbon, Cþ 2F, is stabilising whereas fluorine that is b- to the carbocation centre is destabilising (Chapter 4, Section VI).

+

F

Cl

F

Cl

E-CCl2CF2

Stabilising

E-CF2CCl2

Destabilising

E

Figure 7.50

Systems with perfluoroalkyl groups directly attached to the double bond are particularly unreactive towards electrophiles but reaction of hexafluoropropene (HFP) with SbF5 leads to a perfluoroallyl cation, which then reacts with another molecule of HFP to give a dimer, probably by an electrophilic process [168] (Figure 7.51) that is analogous to that described earlier for 1,1,1-trifluoropropene [169], (Chapter 4, Section VIB). Similar addition and isomerisation reactions, which proceed via carbocationic intermediates, are given in Figure 7.52 [170–172]. Addition of sulphur trioxide is an important step in the process for the production of Nafiont membrane (see Chapter 8, Section IIA) [173]; reaction with chlorotrifluoroethene (CTFE) is not regioselective [174] (Figure 7.53).

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives F

F CF2

F

SbF5

CFCF3

F

CF3 F

F

C3F6

F

½168

+

F

CF2

F

195

F

F

−

shift

F F CF3-CF

F

CFCF(CF3)2

−

CF(CF3)2

F F

F

Figure 7.51

CF2

CFCF3

CF2

i

CF2

F(CF2)2CF

CF3

47 %

½170

i, AlCl3, 25
C

F

+ CF2

SbF5

CF2

½171

F CF2CF3

HCF2CF2CF

SbF5

CF2

FCH

½172

CFCF2CF3

Figure 7.52

F

F

F CF2

CF2

SO3

O

F CF2

CFCl

SO3

i

½173

F SO2

F

F

F Cl

O

SO2

½174

F

Cl

F O

SO2

i, CTFE bubbled through liq. SO3

Figure 7.53

However, sulphur trioxide is also a very strong Lewis acid and reaction with hexafluoropropene proceeds first by fluoride elimination from the allylic position, presumably via the perfluoroallyl cation [152] (Figure 7.54). Tetrafluoroallene is interesting in that, in addition to its susceptibility towards nucleophilic attack discussed earlier, the compound also reacts readily with anhydrous hydrogen

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196

Chapter 7

CF2

CFCF3 i,

F C

SO3

F2C

i or ii CF2

CF2

CFCF2OSO2F

½152

BF3, 50
C, 6hr, (60%);

ii, B(OMe)3, 35
C, 6hr, (52%)

Figure 7.54

fluoride and other hydrogen halides, and it has been reasonably concluded that these reactions probably involve electrophilic attack [175, 176] (Figure 7.55). i CF2

C

CF3CH

CF2

99%

CF2

½175, 176

i, anhyd. HF, −72 to 20
C

Figure 7.55

E

Free-radical additions [177–181]

A generalised free-radical addition process can be described as in Figure 7.56, using the normal terminology for the various steps. A

B

Initiator

A• + B

A

Initiation

A

A• +

A

In

Addition

Propagation

A

+

+

A

B

A

B

A

Chain Transfer

Figure 7.56

If the A–B bond is weak and A2B is in sufficiently high proportion with respect to the alkene, then chain transfer will compete effectively with propagation, allowing overall free-radical addition of A2B to the double bond to occur preferentially (Figure 7.57). A

B +

In

A

B

Figure 7.57

Conversely, when the rate of propagation is faster than chain transfer, products arising from telomerisation and polymerisation are formed in greater concentration. In this section, free-radical addition to fluoroalkenes will be dealt with first, in order to establish

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

197

some ground rules concerning the free-radical addition process, and will be followed by telomerisation and polymerisation.

1

Orientation of addition and rates of reaction

In contrast to ionic reactions, radical additions to unsymmetrical fluoroalkenes are frequently bi-directional; factors that affect the rate and orientation of addition depend on, for example, polar effects, steric effects, radical stabilisation and the character of the attacking radical [182–185]. Free-radical addition to a double bond is a strongly exothermic process, because a p-bond is broken and a s-bond is formed and so, according to the Hammond postulate, early transition states are involved where there is limited bond breaking or making. Consequently, the influence of polar and steric effects becomes significant, in competition with the stability of the developing intermediate radical formed, in determining the orientation and relative rates of addition. Radicals with ‘nucleophilic’ character add to electrophilic alkenes more rapidly than to nucleophilic alkenes whilst, conversely, the rate of addition of electrophilic radicals to electron-rich alkenes is greater than addition to electron-deficient alkenes. To be more sophisticated, we should refer to a high-SOMO (singly occupied molecular orbital; nucleophilic) radical interacting favourably with a low-LUMO (lowest unoccupied molecular orbital; electrophilic) alkene but, for simplicity and brevity, we will continue to use these ‘short-hand’ terms [177]. For instance, compare rates of addition of perfluoroalkyl radicals to ethene and various fluorinated derivatives with their rates of H-atom abstraction from heptane (Table 7.9) [186]. Broadly, reactivity of the alkene decreases with fluorine content, with trifluoromethyl having a large effect. Table 7.9 Relative rates of addition of perfluoroalkyl radicals to alkenes versus their rates of hydrogen-atom abstraction from heptane at 508 C [186] Alkene CH2 5CH2 CH2 5CHF CH2 5CF2 CHF5CF2 CF2 5CF2 CF2 5CFCF3

CF:3 132 30 9 6 8

C2 F:5 340 108 13 9 7 0.33

C3 F:7 290 40 — — <0.3

Addition of radicals to unsymmetrical perfluoroakenes could lead to two possible products (Figure 7.58). Earlier in this chapter we noted that nucleophiles attack the CF2 5 site in a fluorinated alkene exclusively and, in parallel with these observations, nucleophilic radicals, such as CH3 S and carbon-centred radicals, give products arising predominantly from attack at this site (Path 1). Electrophilic radicals such as trifluoromethyl, on the other hand, are less selective and give a mixture of products (Paths 1 and 2) (Figure 7.58). Examples of the regiochemistry of addition of trifluoromethyl to a variety of fluorinated alkenes are given in Table 7.10. l

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Chapter 7

A

CF2

1

ACF2CFCF3

2

CF2CFACF3

AB

ACF2CFBCF3

A

BCF2CFACF3

A

CFCF3 AB

Figure 7.58 Table 7.10 Regiochemistry of trifluoromethyl radical additions to fluoroalkenes: ratio of attack at A:B (Figure 7.58) [182, 184, 187] Alkene

Ratio

A B CH2 5CHF CH2 5CF2 CHF5CHF CH2 5CHCH3 CH2 5CðCH3 Þ2 CH2 5CHCH5CH2 CH2 5CHCF3 CHF5CHCF3 CF2 5CHCH3 CF2 5CHCF3 CF2 5CFCF3

A:B 1:0.09 1:0.05 1:0.05 1:0.1 1:0.08 1:0.01 1:0.01 1:0.33 1:50 1:1.5 1:0.25

A decreasing order of reactivity (towards free-radical addition of methanol) has been observed [188] in the order CF2 5CCl2 > CF2 5CFCl > CFCl5CFCl > CF2 5CHCl, and this is largely consistent with expected effects on the relative stabilities of intermediate radicals after attack at the CF2 sites, where there is a choice. Steric inhibition to attack accounts for the order CF2 5CCl2 > CFCl5CFCl. Frontier orbital theory can also be used to explain the observed rate and orientation patterns [185]. As we have seen (Section IIC, Subsection 2), vinylic fluorine substituents do not affect alkene orbital energies that much in relation to hydrogen, whereas perfluoroalkyl groups lower LUMO energies considerably. Energies of the SOMO (singly occupied molecular orbital) of radicals are increased in radicals containing electrondonating substitutents and so the SOMO (of the attacking radical)–LUMO (of the alkene) interaction is at a maximum with alkenes containing perfluoroalkyl groups in reactions with nucleophilic radicals. The coefficients of the LUMO of the alkene can be used, just as in nucleophilic substitution, to explain the orientation of radical addition. As we have seen, perfluoroalkyl groups polarise the LUMO in such a way as to increase the coefficient at the b-carbon (i.e. the CF2 sites in Table 7.11) and so SOMO–LUMO overlap is greatest at this position. Many examples of free-radical addition to fluoroalkenes have been recorded; some examples are listed in Table 7.11.

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

Table 7.11

199

Free-radical additions to fluoroalkenes

Reaction

Ref. CF2CFH2

CFHCF2H

g rays

[189]

CF2 CFH 60%

40% CF2CFHCF3

i

[45]

+ CF2 CFCF3 i, g rays, or peroxide i

(CH3)2CH2 + CF2 CFCF3

75%

(CH3)2CHCF2CFHCF3

[45] 3%

CH3CH2CH2CF2CFHCF3

i, (t-BuO)2, 140
C

RFH

+ CF2 CFCF3

i

RFH

RFH RFH RFH

i, (t-BuO)2, 140
C

RFH

[45]

RFH

36%

59%

RFH = CF2CFHCF3

CH3OH + CF2 CFCF3

i

93%

CF3CFHCF2CH2OH

[190, 191]

i, (t-BuO)2, 140
C OH + CF2 CFCF3

OH

i

[191] CF2CFHCF3

i, (t-BuO)2, 180
C OH

HO + CF2 CFCF3

OH

i, (t-BuO)2, 140
C

87%

CF2CFHCF3

i

[192] OH

CF2CFHCF3

Contd

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200

Chapter 7

Table 7.11

Contd

Reaction

Ref.

O + CF2 CFCF3

CF2CFHCF3

O

i

[193–195]

70%

i, γ rays, or hν i

CH3(OCH2CH2)nOCH3 + CF2 CFCF3

[196, 197]

RFHCH2[OCH(RFH)CH2]nOCHRFH

i, (t-BuO)2, 140
C

RFH = CF2CFHCF3 F

F

F

RF

F

i

(CH3CH2)2O + [(CF3)2C CHCF2]2

RF H3C

i, γ-rays, rt

O

[198]

CH3

RF = CH(CF3)2 H F

O F

O

γ ray

[194] 83%

O C3H7

C

O H

i

+ CF2 CFCF3

C3H7

[190]

O

O i C

CF2CFHCF3

70%

i, (C6H5CO2)2, 80
C, 16 h.

Ph

C

H

+ CF2 CFCF3

i, (t-BuO)2, 140
C

Ph

CF2CFHCF3 F CF3

+

[199]

F F O CHCl3 + CF2 CFCF3

CCl3CF2CFHCF3

[200]

i, 280
C, 116 h

Contd

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

201

Contd

Table 7.11 Reaction

Ref. Hg/hν

SiH4 + CF2 CFCF3

CF3CHFCF2–SiH3

51%

[201]

F +

F2HC

SiH3

34%

CF3 H F

SiCl3

hν

+ HSiCl3

20
C

+ HSn(CH3)3

F i

(C2H5)2P(O)H + CF2 CF2

[201]

Sn(CH3)3

H F

80%

F

[202]

94%

(C2H5)2P(O)CF2CF2H

33%

[203]

i, (t-BuO)2, 140
C i

CF2 CHCl + SF5Br

F5SCF2CHClBr

73%

[204]

i, 100
C

An interesting process, reminiscent of the Barton reaction, occurs during the radical addition of 7.59A to HFP [205] (Figure 7.59). FH

Me

FH

H

i

F H

H OH

H

F OH

F

OH CF3

F

CF3

7.59A i i, CF2

CFCF3 Me

Figure 7.59

CH2CF2CFHCF3

OH

OH

CF2CFHCF3

CF2CFHCF3

½205

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Chapter 7

2 Telomerisation [178, 206] Telomerisations [207, 208] are regarded as reactions in which a telogen (A2B) and several molecules of a monomer ðR2 C5CR2 Þ react to give short-chain products with, correspondingly, low molecular weights. In these reactions, the propagation step (Figure 7.56) competes with chain transfer, and a number of factors can influence the relative effectiveness of these two processes. In all telomerisations, the distribution of molecular weights increases, i.e. n increases with (a) an increasing rate of free-radical addition to the alkene, (b) a decreasing rate of the atom-transfer step, i.e. the A2B bond is stronger, (c) a higher concentration of alkene relative to the telogen and (d) temperature. As explained earlier in this chapter (Section IIA), the propagation step for the homopolymerisation of tetrafluoroethene is approximately 71 kJmol1 more exothermic than for ethene [2], in spite of adverse polar effects of fluorine substitution on the addition step. It is therefore easy to obtain telomers with tetrafluoroethene and this is also the case with, for example, trifluoroethene, chlorotrifluoroethene and 1,1-difluoroethene. Many telogens (A2B in Figure 7.56) have been used in these processes, including perfluoroalkyl iodides [209], a, v-di-iodoperfluoro- [210] and chlorofluoroalkanes [211], iodine [211], iodine monochloride [212] and perfluoroalkyl bromides [213]. All of the readily available fluorine-containing ethenes have been used as monomers in telomerisation reactions for the production of many telomers, some of which have important commercial applications, e.g. in the synthesis of high-efficiency surfactants and for fire-fighting foams [214]. With CF3 I and CF2 5CF2 , a broad range of telomers is produced unless a considerable excess of the iodide is employed [215]; but with ðCF3 Þ2 CFI as telogen, where the C2I bond is more easily broken [216] (Figure 7.60), the chain length is more easily controlled. (CF3)2CFI

+

CF2=CF2

(4.6 : 1)

175
C

(CF3)2CF(CF2CF2)nI

½216

n = 1 (69%); n = 2 (18%) n = 3 (10%); n = 4 (3%)

Figure 7.60

The effect of the fluoroalkyl iodide on the telomer distribution is illustrated for CH2 5CF2 in Table 7.12, as well as the effect of molar ratio of telogen to alkene and of the reaction temperature. Telomers may be used for further transformations and they are often useful ‘model compounds’ for related polymers, for exploring cross-linking and other processes [217] (Figure 7.61). Telomerisation of hexafluoropropene may be achieved using fluoroalkyl iodides as telogens [218, 219]; this is rather surprising, considering that it is very difficult to achieve homopolymerisation of hexafluoropropene (Figure 7.62). It has been suggested [218] that these reactions may not be radical-chain processes but could involve successive fourcentre additions of fluorocarbon iodides to the olefin (Figure 7.63).

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

Table 7.12

Telomerisation reactions of 1,1-difluoroethene [216]

Fluoroalkyl iodide Molar ratio RF I RF I: CH2 CF2

CF3 I C2 F5 I n-C3 F7 I i-C3 F7 I

203

1 1 1 1 1 1

: : : : : :

1 1 1 1 1 4

Temp. (8 C)

200–210 190 200 185 220 220

CH2

(CF3)2CFI

Composition of RF ðCH2 CF2 Þn I (mol%)

Time Conversion (h) of iodide (%)

41 45 36 36 36 36

35 55 88 88 90 100

n51

2

3

4

5

6

46 92 70 90 87 2

33 6 25 10 13 21

14 2 5 Trace Trace 29

5 — — — — 26

1 — — — — 18

— — — — — 4

180
C

CF2

(CF3)2CF(CH2CF2)nI

½217

SbF5 / 0
C CsF (CF3)2C

CHCF2(CH2CF2)n-1F

(CF3)2CF(CH2CF2)nF

130
C

Figure 7.61

CF2=CFCF3

194
C CF3I

CF3

CF2CFCF3

n

I

½218, 219

n = 1 (47%); n = 2 (23%) n = 3 (19%); n = 4 (8%) n = 5 (4%).

Figure 7.62 RF CF2

I

CF2

CFCF3

Figure 7.63

3

Polymerisation [219a]

Many fluorinated polymers have been prepared using free-radical processes and the intensity of interest in this field stems from the number of unique properties that are bestowed on the polymer by the presence of the carbon–fluorine bonds in a system. For example, excellent resistance to chemically aggressive environments, high thermal stability, low dielectric constant, low flammability and very low surface energies are just some of the properties of fluorinated materials that have been exploited. Uses range from

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Chapter 7

the relatively mundane but important everyday items, like coatings for pans, to crucial materials for the development of supersonic flight and space travel, but the nature of this book dictates that only a sample of the materials available can be illustrated here. The fluorinated ethenes CF2 5CF2 , CF2 5CFH, CF2 5CH2 , CF2 5CFCl and CF2 5CFBr each form homopolymers in conventional free-radical initiation procedures [220] and it is notable that the heat of polymerisation for tetrafluoroethene is much greater than for ethene [2]. Indeed, tetrafluoroethene and trifluoropropene are relatively dangerous monomers to handle because of the risk of explosive polymerisation. In marked contrast, quite drastic conditions are required in order to form a homopolymer from hexafluoropropene (HFP) [221], although commercially successful copolymers of CF2 5CFCF3 with CF2 5CF2 (i.e. FEP) and with CF2 5CH2 (Vitont rubber) have been developed. Polytetrafluoroethene (PTFE), 2ðCF2 CF2 Þn 2 PTFE is polymerised using conventional initiators [220] to give linear polymers whose non-stick properties and chemical inertness are now familiar to all. A disadvantage of PTFE is that it has a very high melt viscosity and cannot be used for melt-processing. Consequently, copolymers of CF2 5CF2 and CF2 5CFCF3 (FEP polymers) are used for this purpose (Figure 7.64). Also, introduction of a perfluoropropoxy group is a more expensive solution to the problem, giving perfluoroalkoxy (PFA) resins. (CF2CF2)x

(CF2CF2)x

(CF2CF)

(CF2CF) OC3F7

CF3 FEP

PFA

Figure 7.64

Recently, amorphous fluoropolymers have been developed in order to obtain highperformance materials with optical clarity for microelectronic etching processes. It is interesting that the monomer perfluoro(2,2-dimethyl-1,3-dioxole) (PDD) (Figure 7.65) is sufficiently reactive to copolymerise with CF2 5CF2 to give copolymers with a high proportion of PDD. This suggests that ether groups, which are isoelectronic with fluorine, have a similar effect to fluorine on reactivity of alkenes towards radicals (Figure 7.65). CF

CF

O

O

F3C

CF3 PDD

CF CF2

CF2

In

CF2

CF

O

O

F3C

CF3

x

CF2 y

Teflon AF®

Figure 7.65

Cytopt (Asahi Glass Co.) is a similar product and is produced by a novel cyclopolymerisation process [222] (Figure 7.66). Calculations suggest that the transition states for forming five-membered rings (Route B) are significantly lower-energy than those for forming six-membered rings (Route A) and therefore it is likely that polymerisation occurs by Route A.

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 205

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives R CF2

CF

O(CF2)2CF

CF2

RCF2

Monomer

Route B

½222

O

Route A

R

F

205

etc.

CF2 F2CR

etc.

F

Polymer

Monomer

O

Figure 7.66

Polychlorotrifluoroethene (PCTFE), 2ðCF2 2CFClÞn 2 This material melts at 2138 C and is therefore melt-processable giving clear films. Polyvinyl fluoride (PVF), 2ðCH2 2CHFÞn 2 PVF films can be made that adhere to various surfaces and are particularly important as protective coatings for both indoor and outdoor applications. Polyvinylidene fluoride (PVDF), 2ðCH2 CF2 Þn 2 This material has excellent mechanical properties and is used extensively as weather resistant coating for aluminium and various outdoor applications. The piezoelectrical properties of the material have been exploited in a range of electronic applications [220]. Vinylidene fluoride/HFP copolymers Vitont was the first of these important systems to be developed as an elastomer suitable for use in aggressive environments. Consequently, this and related materials have made a particularly important contribution to the development of supersonic and space flight. The raw copolymer itself is quite unstable to the loss of hydrogen fluoride and the final product is a result of cross-linking and curing processes. These techniques have been the basis of much study over many years [223].

F

Cycloadditions [2, 224, 225]

1

Formation of four-membered rings

One of the most unusual aspects of organofluorine chemistry is the propensity for fluoroalkenes to form four-membered rings upon dimerisation. For example, tetrafluoroethene dimerises to perfluorocyclobutane, a reaction that is not observed for ethene [226] (Figure 7.67). 2 CF2

Figure 7.67

= CF2

200
C Autoclave

F

½226

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Chapter 7

Codimerisation occurs not only between different fluoroalkenes but also between fluoroalkenes and other unsaturated hydrocarbons. Moreover, some of these codimerisations proceed more readily than the reactions involving only fluorinated alkenes. Examples of addition reactions of fluoroalkenes are shown in Table 7.13. Rate constants have been measured for ½2p þ 2p and ½2p þ 4p cycloadditions involving fluorinated alkenes, employing gas-phase NMR techniques [227]. Table 7.13

Cycloaddition reactions of fluoroalkenes

Reaction

CF2 CFCl

Ref. Cl

130−250
C

[228]

(E/Z = 1:1)

F Cl CF3

(E + Z)

F CF3

[229]

CF3CF CF2 CF3 F

(E + Z)

F3C CF2 CF2 C CF2

[175]

F CF2 F

H

F CF2 CF2

CH2 CH2

H

150
C

40% F

H F

H F

H

F CF2 CF2

[230]

H

(CH2 CH )2

[230] F

H CH CH2

F F H

F CF2 CF2

225
C

35%

HC CH F F

[231]

H

Contd

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

Table 7.13

207

Contd

Reaction

Ref. F

H

F CF2 CFCl

H

100
C

CH2 CHC6H5

[232] F Cl

H C6H5

(CF3)2CF

(CF3)2CF

<0
C

(CF3)2CFC CF

[233] F

F 72%

18% F

CF2

110
C, 7 days

+

F 47%

[234]

A particular driving force appears to be the presence of CF2 5 in the alkene; 1,2difluoroalkenes, 2CF5CF2, are much less reactive in this context but examples have been recorded [235]. Dimerisation of tetrafluoroethene to perfluorocyclobutane takes place at 2008 C whilst the reverse reaction occurs at about 5008 C [226]. Activation energies, measured for the forward and back reactions, indicate that the dimerisation is exothermic by 209 kJmol1 [236], as compared with approximately 67 kJmol1 for the hypothetical dimerisation of ethene, and point to factors which destabilise the fluoroalkene. Similarly, when the DH values for cyclobutene ring opening for hydrocarbon and fluorocarbon systems were compared earlier in this chapter (Table 7.4), it was concluded that fluorine attached to a vinylic carbon atom raises the energy of the system, relative to that for the corresponding hydrocarbon, leading to a lower bond strength in CF2 5CF2 than in ethene [36, 237]. In forming a cyclobutane ring, not only are these repulsive forces removed but, if a CF2 5 was originally present, then stronger carbon–fluorine bonds are formed in 2CF2 2. Therefore, the factors that probably lead to the driving force for fluoroalkenes to dimerise as in Figure 7.68 are: F F

F

2 F

F F

Figure 7.68

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(1) (2) (3)

Chapter 7

Ip repulsion is relieved. F atoms are mutually bond strengthening in the product. Substituents that stabilise di-radical intermediates will activate (see later).

With few exceptions, products are formed which result from a combination of alkenes in a head-to-head manner, or a correspondingly regiospecific manner in codimerisations (see Table 7.13). Furthermore, the reactions are not stereospecific. In considering the mechanism of these reactions it is important to stress that they are [2p þ 2p] additions, which are formally forbidden as thermally induced [2ps þ 2ps] processes according to the well-established Woodward–Hoffman rules for pericyclic reactions. Consequently, it is much more likely that these reactions proceed via a pathway that involves radical intermediates, although concerted processes have been claimed [238]. A process involving di-radical intermediates provides an explanation for the products obtained in the dimerisation of 1,1-dichlorodifluoroethene (Figure 7.69). The reaction pathway is governed by the stability of the intermediate di-radical species and, because chlorine stabilises a radical centre more effectively than fluorine, i.e. compound 7.69B is more stable than 7.69A, then Pathway B, leading to the head-to-head product, is preferred. Pathway A 2 CF2

CCl2

CCl2

CF2

CF2

CCl2

7.69A Pathway B

CF2—CCl2

F2

CF2—CCl2

F2

Cl2 Cl2

7.69B

Figure 7.69

The orientations of other cyclodimerisations may be accounted for in a similar manner (Table 7.13). However, as the difference in the ability of the substituents at each carbon of the alkene to stabilise a radical diminishes, then the selectivity of the process is also reduced. For example, trifluoroethene gives a mixture of products since, in this case, the stabilities of the two intermediate radicals 7.70C and 7.70D are similar (Figure 7.70). H CF2—CFH F

(E + Z isomers)

CF2—CFH H 2 CF2

CFH

7.70C H

CF2—CFH F CFH—CF2 7.70D

Figure 7.70

H

(E + Z isomers)

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

209

The latter reaction also illustrates that these processes are not stereospecific (see also Table 7.13). Studies on the formation of four-membered rings by reaction between tetrafluoroethene and di-deuterioethene led to analogous conclusions and this is further evidence for the formation of di-radical intermediates [239, 240]. Moreover, reactions involving alkenes with geminal capto-dative substituents (e.g. 7.71A and 7.71B which are, of course, especially stabilising for radical intermediates) are both efficient and regiospecific [241] (Figure 7.71).

CF2

CClSPh

C(CN)t-Bu

i

7.71B i, 120
C,

½241

> Cl

<

7.71A

CH2

<

SPh F2

> CN

t-Bu 10hr. SPh F2

Cl CN

88%

t-Bu

Figure 7.71

The energy of the double bond may be raised by other means, e.g. by strain or by antiaromaticity [224]. Miller, a pioneer in the field of organofluorine chemistry, generated tetrakis(trifluoromethyl)cyclobutadiene and showed that it reacts to form a tricyclic dimer [242] which can be converted to the corresponding cubane and cuneane derivatives by ultraviolet radiation [243] (Figure 7.72). When the system is appropriately substituted, cycloaddition may even proceed via zwitterion formation [244] (Figure 7.73).

2

Formation of six-membered rings – Diels–Alder Reactions [245, 246]

In this section we will consider [4 þ 2] cycloaddition reactions in which the fluoroalkene acts as the dienophile. For related reactions involving fluorinated dienes, see Section IIG. Since Diels–Alder reactions are governed by HOMO–LUMO interaction of the diene and dienophile, we should remind ourselves that vinylic fluorine does not much alter the orbital energies compared with hydrogen, whilst perfluoroalkyl groups significantly lower these orbital energies [33]. Consequently, we might expect that vinylic fluorine should have little effect on reactivity, whereas the introduction of allylic fluorine, especially via trifluoromethyl groups, should have a significant effect in comparison with the corresponding hydrocarbon analogues. We have seen (Table 7.13) that in reactions between fluoroalkenes and dienes, [2 þ 2] cycloaddition as opposed to [4 þ 2] cycloaddition is the dominant reaction [246, 247], and systematic studies performed on reactions of this type, such as that between 1,1-dichlorodifluoroethene and isoprene, provide a strong case for the intermediacy of

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 210

210

Chapter 7 CF3

F3C

Br F F3C

CF3

F3C

F3C

CF3

F3C

CF3

Li, −20
C

CF3 CF3

CF3

½243

CF3 CF3

F3C

CF3 F

F3C

CF3 CF3

CF3

F3C

CF2

CF3 CF3

300
C

300
C hν

hν

(CF3)8

(CF3)8

300
C

(CF3)8

Figure 7.72 (CF3)2C

C(CN)2

CH2

CHOC2H5

(CF3)2C H2C

C(CN)2

½244

CH.OC2H5

F3C

CN

F3C H

CN H OC2H5

H 95%

Figure 7.73

di-radicals [248] (Figure 7.74). A methyl group would be expected to make a greater contribution to the stability of the allyl system in 7.74B than in 7.74A; this is consistent with the product ratio observed. Nevertheless, some Diels–Alder reactions between fluoroalkenes and dienes have been recorded with significant amounts of product derived from Diels–Alder addition when the diene is in the cis conformation [246, 249] (Figure 7.75).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 211

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives CF2CCl2 80
C

+

+

+

½248

Cl2

CF2 — CCl2

CF2 — CCl2 7.74 B

1.6%

7.74 A

F2

F2

211

F2

Cl2

Cl2 83%

15%

Figure 7.74

+ CF2

F2

F2

475
C

CF2

+ F2

½246, 249

F2 2:1

Figure 7.75

The thermal addition of trifluoroethene to cyclopentadiene at and below 1228 C yields a 1,4-cycloadduct, with less than 0.1% of 1,2-cycloadduct, whereas a photosensitised reaction between these two reactants (a di-radical process) leads to a product consisting of 87% of the 1,2-cycloadduct and 13% of the 1,4-cycloadduct [250]. These contrasting results led to the conclusion that the thermally induced Diels–Alder product arises from a normal concerted process and it is probable that, in general, whilst the 1,2-cycloadditions and 1,4-Diels–Alder additions are competing processes, they are mechanistically unrelated. Fluoroalkenes possessing perfluoroalkyl substituents, which reduce the energy of the frontier orbitals, undergo Diels–Alder reactions, as shown in Figure 7.76 [251, 252]. O

O

CF2

i + CF2

CFCF3

F F

i, 120
C, 16 h., Et2O

35%

½251

F

F + CF3CF

CFCF3

260
C 30 h

CF3 CF3

Figure 7.76

F

42%

½252

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Chapter 7

Fluoroalkenes that have significant ring strain in the ground state undergo Diels–Alder reactions much more readily, due to the enhanced relief of this strain upon [4 þ 2] cycloaddition as opposed to [2 þ 2] addition (Table 7.14) Table 7.14

Diels–Alder additions to fluorinated alkenes

Reaction

Ref. F F

F

72%

80
C

[253]

F

H2

F

F

O

F

O

F

H2

O

O

[254]

100%

F2 F10 Me

Cl F F

F

Cl

Me

F2

Me

89%

170
C, 48 h Me

F F

100
C

CF2 +

[255]

F2

[256]

F F F

F

100
C

F

+

F

30%

[257]

F

3 Formation of five-membered rings – 1,3-dipolar cycloaddition reactions A number of 1,3-dipolar cycloadditions to fluoroalkenes have been reported [245]; some examples are listed in Table 7.15. Addition of diazomethane to fluoroalkenes [72] follows the order of reactivity ðRF Þ2 C5CðRF Þ2 > ðRF Þ2 C5CFRF > ðRF Þ2 C5CF2 , RF CF5CFRF ðRF ¼ perfluoroalkyl). In reactions involving unsymmetrical fluoroalkenes the additions are highly regiospecific, with the carbon atom of the dipole becoming attached to the site most susceptible

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213

1,3-Dipolar cycloaddition reactions involving fluoroalkenes

Table 7.15 Reaction

Ref.

CF3

C2F5

CF3

F

+

CH2—N N

C2F5

C2F5

CF3

H

N CF3

+ CH2—N N

N

H

i

C2F5

CF3 F

H

N

93%

CF3 C2F5 CF3

i, Et2O, rt

C2F5

N

H H

N CF3 CF3

CF3 +

CF3

CF3

H N

H CF3

N

H CF3 CF3

CH2Ph

N

N

i

CF2 + PhCH2N3

H

N

i, Et2O, rt

87% CF3

F

CF3

[198]

H CF3

i

CH2—N N

CF3

[72, 258]

94%

i, Et2O, rt

CF3

N

H i

F

i, 190
C, 16 h

[259]

CF3

F N

i + CH2—N N

F

i, Et2O, rt, 14 days

N

55%

[72]

F

to nucleophilic attack. These concerted reactions probably proceed with some character of nucleophilic attack and the orientation of attack can be accounted for in terms of the frontier orbital approach discussed in Section IIC, Subsection 2 [72] (Figure 7.77). (RF)2C

CF(RF)

N N

CH2

Figure 7.77

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Chapter 7

4 Cycloadditions involving heteroatoms In the light of the foregoing discussion it may be expected that fluoroalkenes participate in cycloaddition reactions with unsaturated systems containing heteroatoms [260], e.g. nitroso compounds [261], sulphur trioxide [262], sulphur dioxide [263], nitriles [264] and so on (Figure 7.78). F3C N F

20
C CF2

CF2

O

F

CF3NO −45
to 20
C

N

F

O

CF2

n

O

O CF2

+ SO3

0
C R

R = CH2ClCHClCH2-

CF2

CF2

SO2

i

S

O

C

C

F

F

F

F

F

F

½262

44%

F S

i, CF2Cl2, N2, hν, −32 to 90
C

64%

CF2

CF3

RCF

½261

62%

F

FCOCF2SOF 80%

O

CF3 F

CF3CN

½263

O

F

F N

N

40%

½264

CF3

Figure 7.78

G

Polyfluorinated conjugated dienes

1 Synthesis Many of the synthetic approaches that are used for the preparation of fluoroalkenes can be adopted for the synthesis of polyfluorodienes. Examples of other processes such as reductive coupling methods and syntheses based on organometallic precursors [265] or phosphorous ylids are also included in Table 7.16.

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

Table 7.16

215

Synthesis of fluorodienes and polymers

Reaction

Ref.

Dehydrohalogenation H

CF3

H CF 3

CF2

CF3

CF3 i, t-BuOK/t-BuOH

CF2

i

CF3

CF3

i

(CF3)2CFCH2CF2

[266]

(CF3)2C CHCF2

2

70%

2

[267]

i, CsF, 150
C, Sealed Tube

Dehalogenation Zn

BrCF2CClFCClFCF2Br CF3

CF2 CFCF CF2 CF3

F Cl CF2Cl

CF3

F F

i CF3 F

F

40%

[269]

F

i, Zn, 120
C, diglyme CF3

CF3

C2F5

C2F5

CF3

CF3

i F

F CF3

Me2N i, Me N 2

F

F

NMe2 NMe2

90%

[270]

CF3

, CH2Cl2, rt

F

i

79%

F

F

[268]

78%

[270]

F i, Na, Hg (0.5% w/w), water cooling

O

Cl

O

O

i

ii

F

[271]

(FCl)6 i, F2, CF2ClCFCl2

ii, Cu Bronze

Contd

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216

Chapter 7

Table 7.16

Contd

Reaction

Ref.

Decarboxylation i

25−37%

CF2 CFCF CF2 +

NaO2C(CF2)4CO2Na

[272]

CF2 CF(CF2)2CO2Na

i, 450
C, 0.01 mm

Reductive coupling Cl

I i

F

75%

F

F

[273]

Cl Cl i, Cu powder, DMF, 135
C

F

F

i F

F

I

+

F I

[273] F

F

F

i, Cu powder, DMF, 135
C 34%

50%

hν F

F F

F

[274] Anti : Syn = 20 : 1

CF3

F

CF3

F

Cu

Ph

F

CF3

F

Ph

+

[265, 275]

F

I

F

CF3

CF3

CF3 i F

F

F

75%

[276]

CF3 i, PPh3, CH3CN, 25
C

2 Reactions Fluorinated dienes, like fluoroalkenes, are very susceptible to nucleophilic attack [90, 91]; some examples of nucleophilic substitution processes are given in Table 7.17. Examples of rearrangements and other reactions are also listed. An early demonstration that

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

217

Reactions of polyfluorinated dienes

Table 7.17 Reaction

Ref.

Nucleophilic attack OPh i

F

F

F

+ PhOH

F PhO

i, KF, CH3CN, rt CF3

CF3

F

CF3

+ K2S

DMF rt

72%

[73] S (CF ) 3 4

CF3

F

H

F

CF3

[73]

58%

F F

F

CF3

MeOH rt

CF3

CF3

[269, 279] F

F

CF2OMe

MeO F

F

MeOH rt

F

[73]

MeO F

CF3 CF3

CF3

CF2

CF2

O

F CO2Et

O

i

CF2

+

[280] Na +

OEt

F

O

Me

F

i, Tetraglyme, rt, 17 h

CF3

CF3 CF3

CF3 i

F CF3

70%

O

+ t-BuOOH

F

O F

CF3

CF3

F

CF3

[281]

i, BuLi, THF, −78
C to rt

Rearrangements CF3

F

F F

0 to 5
C

CF3 F

F

CF3

SbF5

CF3 F F

[269]

F

Contd

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218

Chapter 7

Table 7.17

Contd

Reaction

Ref.

F

F CF2

CF2 F

hν 85
C, 5 h

F F

+

F

F

[282]

CF2

F

64%

36%

Cycloadditions F F

CF2 HC CCPh

F2C

F

Dioxane 60
C

F

F

+ H

CF2

Ph

Ph

F

[283]

H 38%

4%

1,4-cycloadditions of fluorinated dienes may occur involved perfluorocyclo-1,3-hexadiene, as shown in Figure 7.79. CO.CH3 Heat F

+

CH2

½277

F

CHCO.CH3

H H

Figure 7.79

The acceptor properties of some cyclic dienes are sufficient for stable charge-transfer salts to be isolated (Figure 7.80). +

F

F

+ [C5Me5]2Fe

F

F

[C5Me5]2Fe

½278

Figure 7.80

3 Perfluoroallenes Perfluoroallenes are also attacked by nucleophiles and undergo cycloaddition reactions, as shown in Table 7.18.

III

FLUOROALKYNES AND (FLUOROALKYL)ALKYNES

A Introduction and synthesis Fluorine directly attached to a carbon–carbon triple bond raises the energy of the system due to repulsion between the p-electrons and the non-bonding electron pairs on fluorine, as we have discussed earlier (Figure 7.10).

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

219

Reactions of perfluoroallenes

Table 7.18 Reaction

Ref. CF3

CF3

F

CsF

CCCF2

F3C

F

(CF3)2CF

F

F3C

CF3

CF3

F

F3C

F

72%

[284]

F 18%

CF2

CF2=C=CF2 + PhCHN2

F

Ph

i

[285]

F N

i, benzene, rt

N

78%

H

CF2=C=CF2 +

N

F

O

Ph + N

N

i O

N

Ph

[286]

CF3 63%

i, xylene, 120
C

Indeed, monofluoroethyne, obtained by the pyrolysis of monofluoromaleic anhydride, is dangerously explosive whilst difluoroethyne has not been isolated, although claims to its preparation have been reported [287] (Figure 7.81). F

O F O

650
C 1-2mm

HC

CF

½287

+ CO + CO2 F

F

O

Figure 7.81

However, perfluoroalkyl substituents lower the energy of the system; for example, perfluoropropyne is considerably more stable than the fluoroalkynes referred to above [288] (Figure 7.82). Perfluorodialkylalkynes, in which fluorine lone-pair–p-electron repulsions are absent, are quite stable, and the chemistry of these substrates has been well developed [41, 289– 291]. Perfluoro-2-butyne is the most important member of this class of compounds that can be obtained by a reasonably direct route [292] (Figure 7.83). Hexafluoro-2-butyne has also been obtained by routes involving fluoride-ion processes, such as by using a fluorocarbon ‘solvent’ [53] or by passing perfluorocyclobutene over a bed of caesium fluoride or potassium fluoride [293] (Figure 7.84).

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220

Chapter 7 i

CF2Br2 + CH2=CF2

ii

CF2BrCH2CF2Br

CF2BrCH=CF2 86%

½288

i, Bz2O2, 110
C; ii, C, 300C; iii, hν, Br2 iii

CF3C

CF

Zn dioxane

CF3CBr=CFBr

AlBr3

CF2BrCHBrCF2Br

Figure 7.82

i

CCl2=CClCCl=CCl2

CF3CCl=CClCF3

½292

85% i, SbF3, SbF3Cl2, 115
C ii

ii, Zn, (CH3CO)2O, reflux CF3C

63%

CCF3

Figure 7.83

i

CCl2=CClCCl=CCl2

CF3CH=CFCF3

ii CF3C

i, Fluorocarbon, sulpholan (25% v:v), KF ii, Molecular Sieve

F

CCF3

½53

56%

CF2 i

F

CF3C F

CF2

F

CCF3

½293

80%−90%

i, CsF or KF, 510−590
C, Flow system in N2

Figure 7.84

A recent direct route from CF3 CH2 CF2 H (hydrofluorocarbon 245fa) to the lithium salt now makes the trifluoropropyne ‘building block’ very accessible for many potential developments [294] (Figure 7.85). Other syntheses of a variety of fluoroalkynes are given in Table 7.19 where, in many cases, the synthetic approaches to these compounds can be seen to be adaptations of methods for the preparation of fluoroalkenes.

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives i, ii CF3CH2CF2H

221

i, ii

CF3CH=CHF

CF3C

CH

½294 i

CF3C

PhCHO

CCH(OH)Ph

CF3C

CLi

60% Ph3SnCl CF3C

i, n−BuLi ii, −LiF

CSnPh3

84%

Figure 7.85 Synthesis of fluoroalkynes

Table 7.19 Reaction

Ref. i

CF2=CH2

FC CH

90%

[295]

i, s-BuLi, −110
C to −80
C i

CF3CH=CICH3

CF3C CCH3

45%

[296]

i, KF, crown ether, dioxane i C3F7C CZnCl

C3F7CCl2CCl3

HCl

CF3C CH

[297]

77% i, Zn, DMF, 90−100
C RF RF

RF N

hν rt

N

RFC CRF

[298]

+ RFC N

N RF = CF(CF3)2

CH3(CH2)5C CSnMe3

+ C6F13I

70
C 6h

C6H13C CC6H13

[299]

55%

C3F7I +

HC CH

220
C

C3F7CH=CHI

KOH

i

i, C3F7I, 220
C C3F7C CC3F7

C3H7C CH

[300] KOH

C3F7CI=CHC3F7

Contd

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Chapter 7

Table 7.19

Contd

Reaction

Ref. HO

CF3

p-ClC6H4

Cl Cl

CF3

H

i p-ClC6H4

ii

p-C6H4C CCF3

[301]

Cl 81%

i, Ac2O, Et3N, Zn, DMF; ii, NaNH2, t-BuOH, benzene, rt i PhC CLi

PhC CC8F17

+ C8F17IPhOTf

[302]

66%

i, THF, −78
C

B Reactions Formation of the lithium derivative of trifluoropropyne was described in the preceding section [294] and the various acetylides, RF C;CM, had been prepared previously (e.g. M ¼ Cu, Ag, Hg; RF ¼ CF3 , C2 F5 , CF3 CH2 ) [289]. However, most studies concerning the reactions of perfluoroalkynes [291] have centred on the use of perfluoro-2-butyne, as this is commercially available.

1 Perfluoro-2-butyne [289, 291] Formation of polymers and oligomers: When perfluoro-2-butyne is heated, either alone or with halogen compounds or a metal carbonyl, hexakis(trifluoromethyl)benzene is obtained [303–306] (Figure 7.86). This is a very interesting compound that gives stable valence isomers on irradiation with ultraviolet light (see Chapter 9, Section IIE, Subsection 4). CF3 CF3

F3C CF3C

CCF3

375
C

hν F3C

Stable valence isomers

½303306

CF3 CF3

Figure 7.86

A high-molecular-weight, insoluble polymer is obtained when perfluoro-2-butyne is subjected to various initiators for free-radical polymerisation (Figure 7.87). The off-white colour of this material is remarkable for a polyacetylene! [307, 308]. Indeed, it is largely ignored in discussions on polyacetylenes because, of course, the fact that it is not coloured also means that the system is not conjugated: the trifluoromethyl groups keep the p-systems out of plane relative to each other.

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives hν CF3C

-C(CF3)=C(CF3)-

CCF3

223

½307, 308

n

Figure 7.87

Reactions with nucleophiles: The most striking feature about this alkyne is that it is extremely electrophilic in nature, and electrophilic additions are suppressed whilst nucleophilic additions proceed with ease in reactions with a wide range of nucleophilic species (cf. fluoroalkenes) [309, 310] (Figure 7.88). F3C

NaOBu n–C4H9OH + CF3C

CCF3

H 89%

20
C

n-BuO

CF3

F3C CF3C

CCF3

+

OH

½309

½310

O

NaOH 50
C F3C

O

F3C CF3

Figure 7.88

Fluoride-ion-induced reactions: A similar polymer to that in Figure 7.87 is obtained upon anionic polymerisation of hexafluoro-2-butyne initiated by fluoride ion in a solvent [311–313] (Figure 7.89). This is a clear example of an anionic polymerisation of an unsaturated fluorocarbon, although the growing anion can be trapped by a sufficiently reactive system [291, 314], such as pentafluoropyridine [315] (Figure 7.90). There is little difference between the ultraviolet spectra of 7.90A and 7.90B, confirming that conjugation in the polyene system is inhibited by steric effects.

CF3C

CCF3

i

i, CsF, Sulpholan

CF3CFCCF3

½311313

C4F6

CF3CFC(CF3)C(CF3)CCF3 C4F6

F

Figure 7.89

CF3CC(CF3)

etc.

n

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224

Chapter 7 F CF3

F3C

½315

7.90A F N F CF3C

i

CF3F=CCF3

CCF3

C(CF3)=C(CF3)nF F

i =

F

N

7.90B

N

Figure 7.90

An equivalent polymer is also obtained from perfluorobutadiene in the presence of fluoride ion; this is a further demonstration of the propensity of systems to rearrange to reduce the number of fluorine atoms attached to vinyl sites [315, 316] (Figure 7.91). F

CF2=CF

i

i CF3C

2

C(CF3)=C(CF3)

CCF3

n

½315, 316

i, CsF, Sulpholan, 100
C

Figure 7.91

Cycloadditions [40]: Perfluoro-2-butyne is a highly reactive dienophile and many [4 þ 2] cycloaddition and 1,3-dipolar addition reactions involving this alkyne have been reported (Table 7.20). Moreover, [2 þ 2] additions with hydrocarbon alkenes are possible (Table 7.20).

Cycloaddition reactions with perfluoro-2-butyne

Table 7.20 Reaction

Ref. COPh

COCH3

N

N +

i

CF3C CCF3

100%

[317]

CF3 CF3

i, THF, 100
C

CF3C CCF3 + PhN3

50
C

N N

CF3

Ph N

80%

[318]

CF3

Contd

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

Table 7.20

225

Contd

Reaction

Ref. CF3 F3C 200
C

CH3

H3C

CF3C CCF3

[319]

10 h H3C

CH3

O CF3

100
C CF3C CCF3

O 6h H3C

CH3

CF3

OH CF3

CF3

[320]

i

ii

F3C

CH3

CH2=CH2

O F3C CH3

i, BF3.Et2O ii, H2, Pt/C, 400
C CF3

CF3C CCF3

∆

F3C

[321]

Polyacetylene

Heptafluoro-2-butene, which is readily available in a laboratory synthesis from hexachlorobutadiene, may be used as a synthon for perfluoro-2-butyne in cycloaddition reactions where in situ elimination occurs [322] (Figure 7.92). Reaction with difluorocarbene leads to the formation of novel cyclopropene and bicyclobutane systems [323] (Figure 7.93), and similar reactions are observed using polyfluoroalkyne derivatives of some metals [324]. Reactions with sulphur atoms alone give a variety of cyclic products, depending on the conditions [325], but when iodine is also present the potentially aromatic compound

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226

Chapter 7 CF3

CF3CH=CFCF3

F3C

−HF

½322

CF3 91% CF3

Figure 7.92

F CF3C

CCF3

[CF2]

F3C

CF3

100
C

[CF2]

F

F3C

CF3

100
C F

F

F

½323

F 25%

Figure 7.93

7.94B is produced which is a rare, and probably unique, example of the dithiete system [326] (Figure 7.94). S

(CF3)4 CF3C

CCF3

S

S

½326

I2 S

CF3

F3C

7.94A 11% F3C

F3C

7.94B 26% S

S

CF3

S

S

CF3

7.94C 29%

Figure 7.94

Free-radical additions: Free-radical addition reactions involving perfluoro-2-butyne are also possible, as indicated in Figure 7.95 [327, 328].

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

227

CF3 γ CH3CHO

+ CF3C

O

CF3 CF3

H

C3F7I

+

CF3C

CCF3

220
C 7 days

½327

30%

CCF3

CF3CIC(CF3)C3F7 Z:E

68%

½328

3:4

Figure 7.95

REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

G. Sandford, Tetrahedron, 2003, 59, 437. B.E. Smart in The Chemistry of Functional Groups. Supplement D: Fluorocarbons, ed. S. Patai and Z. Rappoport, John Wiley and Sons, New York, 1983, p. 603. B.E. Smart in Fluorinated Organic Molecules, ed. J.F. Liebman and A. Greenberg, VCH, Deerfield Beach, 1986, p. 141. D.F. McMillen and D.M. Golden, Ann. Rev. Phys. Chem., 1982, 33, 493. L. Pauling, The Nature of the Chemical Bond, Cornell Univ. Press, Ithaca, NY, 1960. N.C. Baird, Can. J. Chem., 1983, 61, 1567. E.T. McBee, Ind. Eng. Chem., 1947, 19, 237. M. Hudlicky, Chemistry of Organic Fluorine Compounds, Pergamon, Oxford, 1961. T.J. Brice in Fluorine Chemistry, ed. J.H. Simons, Academic Press, New York, 1950, p. 436. J.G. Riess, Chem. Rev., 2001, 101, 2797. R. Taylor, Chemistry – A European Journal, 2001, 7, 4074. W.A. Sheppard and C.M. Sharts, Organic Fluorine Chemistry, Benjamin, New York, 1969. A.M.G. MacDonald in Comprehensive Analytical Chemistry, Vol. 1B, ed. C.L. Wilson and D.W. Wilson, Elsevier, London, 1960, p. 547. S. Tasker, R.D. Chambers and J.P.S. Badyal, J. Phys. Chem., 1994, 98, 124421. J.L. Kiplinger and T.G. Richmond, J. Am. Chem. Soc., 1996, 118, 1805. B.K. Bennett, R.G. Harrison and T.G. Richmond, J. Am. Chem. Soc., 1994, 116, 11165. J.A. Marsella, A.G. Gilicinski, A.M. Coughlin and G.P. Pez, J. Org. Chem., 1992, 57, 2856. D.D. MacNicol and C.D. Robertson, Nature, 1988, 332, 59. J. Burdeniuc, W. Chupka and R.H. Crabtree, J. Am. Chem. Soc., 1995, 117, 10119. W.H. Pearlson and L.J. Hals, US Pat. 2 617 836 (1952); Chem. Abstr., 1952, 47, 8770. E.E. Lewis and M.A. Naylor, J. Am. Chem. Soc., 1947, 69, 1968. M. Hudlicky, Chemistry of Organic Fluorine Compounds 2nd (revised) edition, Ellis Horwood, Chichester, 1992. J. Rabai, S. Zoltan and I.T. Horva´th in Handbook of Green Chemistry, ed. J. Clark and D. Macquarrie, Blackwell Science, Oxford, 2002, p. 502. D.P. Curran, S. Hadida, A. Studer, M. He, S.-Y. Kim, Z. Luo, M. Larhed, A. Hallberg and B. Linclau, Comb. Chem., 2000, 327. I.T. Horva´th, Acc. Chem. Res., 1998, 31, 641. D.F. Foster, D. Gudmunsen, D.J. Adams, A.M. Stuart, E.G. Hope, D.J. Cole-Hamilton, G.P. Schwarz and P. Pogorzelec, Tetrahedron, 2002, 58, 3901.

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27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

63 64

Chapter 7

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N.S. Rao and B.E. Baker in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 321. R.N. Haszeldine, J. Fluorine Chem., 1953, 3761. R.D. Chambers, J. Hutchinson, R.H. Mobbs and W.K.R. Musgrave, Tetrahedron, 1964, 20, 497. R.D. Chambers, G.C. Apsey, P. Odello, G. Moggi and W. Navarrini, IUPAC Macromolecular Symposia 82, Fluorinated Polymers, Prague, 1994, ed. J. Kahovec. H. Hauptschein, M. Braid and F.E. Lawlor, J. Am. Chem. Soc., 1957, 79, 2549. J. Balague, B. Ameduri, B. Boutevin and G. Caporiccio, J. Fluorine Chem., 1995, 74, 49. G. Hougham (ed.) Fluoropolymers, Academic/Plenum Publishers, New York, 1999. A.E. Feiring in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 339. H.S. Eleuterio, US Pat 2 958 685 (1960); Chem. Abstr., 1961, 55, 6041. M. Nakamura, N. Sugiyama, Y. Etoh, K. Aosaka and J. Endo, J. Chem. Soc. Jpn, Chem. Ind. Chem., 2001, 659. A.L. Logothetis in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 373. B.E. Smart in Chemistry of Organic Fluorine Compounds II, ed. M. Hudlicky and A.E. Pavlath, ACS Monograph 187, Washington DC, 1995, p. 767. M. Hudlicky, Chemistry of Organic Fluorine Compounds, 2nd (revised) edition, Ellis Horwood, Chichester, 1992. J. Harmon, US Pat. 2 404 374 (1946); Chem. Abstr., 1946, 40, 7234. A.B. Shtarov, P.J. Krusic, B. Smart and W.R. Dolbier, J. Am. Chem. Soc., 2001, 123, 9956. J.D. Park, K.V. Holler and J.R. Lacher, J. Org. Chem., 1960, 25, 990. M. Hauptschein, A.H. Fainberg and M. Braid, J. Am. Chem. Soc., 1958, 80, 842. D.C. Coffman, P.L. Barrick, R.D. Cramer and M.S. Raasch, J. Am. Chem. Soc., 1949, 71, 490. J.L. Anderson, R.E. Putnam and W.H. Sharkey, J. Am. Chem. Soc., 1961, 83, 382. P. Tarrant, R.W. Johnson and W.S. Brey, J. Org. Chem., 1962, 27, 602. R.D. Chambers, T. Sheppard, M. Tamura and M.R. Bryce, J. Chem. Soc., Chem. Commun., 1989, 1657. W.R. Dolbier, M. Seabury, D. Daly and B.E. Smart, J. Org. Chem., 1986, 51, 974. P.D. Bartlett and J.J.B. Mallet, J. Am. Chem. Soc., 1976, 98, 143. B. Atkinson and A.B. Trenwith, J. Chem. Soc., 1953, 2082. S.J. Getty and W.T. Borden, J. Am. Chem. Soc., 1991, 113, 4334. D.W. Roberts, Tetrahedron, 1985, 41, 5529. P.D. Bartlett, G.M. Cohen, S.P. Elliot, K. Hummel, R.A. Minns, C.M. Sharts and J.Y. Fukunaga, J. Am. Chem. Soc., 1972, 94, 2899. P.D. Bartlett, K. Hummel, S.P. Elliot and R.A. Minns, J. Am. Chem. Soc., 1972, 94, 2898. C. DeCock, S. Piettre, F. Lahousse, Z. Janousek, R. Merenyi and H.G. Viehe, Tetrahedron, 1985, 41, 4183. W.T. Miller, R.J. Hummel and L.F. Pelosi, J. Am. Chem. Soc., 1973, 95, 6850. W.T. Miller and L.F. Pelosi, J. Am. Chem. Soc., 1976, 98, 4311. R. Huisgen and R. Bruckner, Tetrahedron Lett., 1990, 31, 2553. W.R. Dolbier in Chemistry of Organic Fluorine Compounds II, ed. M. Hudlicky and A.E. Pavlath, ACS Monograph 187, Washington DC, 1995, p. 797. D.R.A. Perry, Fluorine Chem. Rev., 1967, 1, 253. W.H. Sharkey, Fluorine Chem. Rev., 1968, 2, 1. P.D. Bartlett, G.E.H. Wallbillich, A.S. Wingrove, J.S. Swenton, L.K. Montgomery and B.D. Kramer, J. Am. Chem. Soc., 1968, 90, 2049. J.J. Drysdale, W.W. Gilbert, H.K. Sinclair and W.H. Sharkey, J. Am. Chem. Soc., 1958, 80, 245.

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250 P.D. Bartlett, Quart. Rev., 1970, 24, 473. 251 V.A. Albekov, A.F. Benda, A.F. Gontar, G.A. Sokolskii and I.L. Knunyants, Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1988, 37, 777. 252 V.A. Albekov, A.F. Benda, S.G.A. Gontar, and I.L. Knunyants, Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1988, 37, 785. 253 A.E. Bayliff, M.R. Bryce, R.D. Chambers, J.R. Kirk and G. Taylor, J. Chem. Soc., Perkin Trans. 1, 1985, 1191. 254 Y. He, C.P. Junk, J.J. Cawley and D.M. Lemal, J. Am. Chem. Soc., 2003, 125, 5590. 255 D.J. Burton and D.A. Link, J. Fluorine Chem., 1983, 22, 397. 256 B.E. Smart, J. Am. Chem. Soc., 1974, 96, 929. 257 P.B. Sargeant and C.G. Krespan, J. Am. Chem. Soc., 1969, 91, 415. 258 M.R. Bryce, R.D. Chambers and G. Taylor, J. Chem. Soc., Chem. Commun., 1983, 5. 259 Y.V. Zeifman and L.T. Lantseva, Bull. Acad. Sci., USSR, 1986, 35, 248. 260 I.L. Knunyants and G.A. Sokolski, Angew. Chem. Int. Ed. Engl., 1972, 11, 583. 261 D. Barr and R.N. Haszeldine, J. Chem. Soc., 1955, 2532. 262 J. Mohtasham, G.L. Gard, Z.Y. Yang and D.J. Burton, J. Fluorine Chem., 1990, 50, 31. 263 A.Y. Yakubovich, S.M. Rozenshstein, S.E. Vasyukov, B.I. Tetel’baum and V.I. Yakutin, J. Gen. Chem. USSR, 1966, 36, 740. 264 L.P. Anderson, W.J. Feast and W.K.R. Musgrave, J. Chem. Soc. (C), 1969, 2559. 265 D.J. Burton, Z.Y. Yang and P.A. Morken, Tetrahedron, 1994, 50, 2993. 266 G.S. Krashnikova, L.S. German and I.L. Knunyants, Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1973, 22, 459. 267 G. Apsey, R.D. Chambers and M. Salisbury, J. Fluorine Chem., 1988, 40, 261. 268 V. Dedek and Z. Chvatal, J. Fluorine Chem., 1986, 31, 363. 269 V.A. Petrov, G.G. Belenkii and L.S. German, Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1981, 30, 1920. 270 M.W. Briscoe, R.D. Chambers, S.J. Mullins, T. Nakamura, J.F.S. Vaughan and F.G. Drakesmith, J. Chem. Soc., Perkin Trans. 1, 1994, 3115. 271 Y. Lou, Y. He, J.T. Kendall and D.M. Lemal, J. Org. Chem., 2003, 68, 3891. 272 R.N. Haszeldine, J. Chem. Soc., 1954, 4026. 273 R.L. Soulen, S.K. Choi and J.D. Park, J. Fluorine Chem., 1973, 3, 141. 274 D. Lemal in Fluorine Chemistry at the Millennium, ed. R.E. Banks, Elsevier, Amsterdam, 2000, p. 297. 275 D.J. Burton and S.W. Hansen, J. Am. Chem. Soc., 1986, 108, 4229. 276 A.A. Stepanov, G.Y. Bekker, A.P. Kurbakova, L.A. Leites and I.N. Rozhkov, Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1981, 21, 2746. 277 R.D. Chambers, W.K.R. Musgrave and D.A. Pyke, Chem. Ind., 1964, 564. 278 M.W. Briscoe, R.D. Chambers, W. Clegg, V.C. Gibson, S.J. Mullins and J.F.S. Vaughn, J. Fluorine Chem., 1996, 76, 1. 279 I. Linhart and V. Dedek, Collect. Czech. Chem. Commun., 1985, 50, 1737. 280 M.R. Bryce, R.D. Chambers, A.A. Lindley and H.C. Fielding, J. Chem. Soc., Perkin Trans. 1, 1983, 2451. 281 R.D. Chambers, J.F.S. Vaughan and S.J. Mullins, J. Chem. Soc., Chem. Commun., 1995, 629. 282 Z. Chvatal and V. Dedek, J. Fluorine Chem., 1993, 63, 185. 283 N.B. Kazmina, A.P. Kurbakova, L.A. Leitas, B.A. Kvasov and E.J. Mysov, Zh. Org. Khim., 1986, 55, 1500. 284 P.W.L. Bosbury, R. Fields and R.N. Haszeldine, J. Chem. Soc., Perkin Trans. 1, 1978, 422. 285 G.B. Blackwell, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc., Perkin Trans. 1, 1983, 1. 286 G.B. Blackwell, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc., Perkin Trans. 1, 1982, 2207. 287 B.E. Smart in The Chemistry of Functional Groups. Supplement D, Fluorocarbons, ed. S. Patai and Z. Rappoport, John Wiley and Sons, New York, 1983, p. 613.

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328

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R.E. Banks, M.G. Barlow, W.D. Davies, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc. (C), 1969, 1104. M.I. Bruce and W.R. Cullen, Fluorine Chem. Rev., 1969, 4, 79. H. Muramatsu and K. Inukai, J. Synth. Org. Chem. Jpn., 1973, 31, 466. E.S. Turbanova and A.A. Petrov, Russ. Chem. Rev., 1991, 60, 501. A.L. Henne and W.G. Finnegan, J. Am. Chem. Soc., 1949, 71, 298. R.D. Chambers, C.G.P. Jones, G. Taylor and R.L. Powell, J. Chem. Soc., Chem. Commun., 1979, 964. A.K. Brisdon and I.R. Crossley, J. Chem. Soc., Chem. Commun., 2002, 2420. R. Sauvetre and J.F. Normant, Tetrahedron Lett., 1982, 23, 4325. J.J. Mielcarek, J.G. Morse and K.W. Morse, J. Fluorine Chem., 1978, 12, 321. D.J. Burton and T.D. Spawn, J. Fluorine Chem., 1988, 38, 119. R.D. Chambers, T. Shepherd, M. Tamura and P. Hoare, J. Chem. Soc., Perkin Trans. 1, 1990, 983. S. Matsubara, M. Mitani and K. Utimoto, Tetrahedron Lett., 1987, 28, 5857. M. Hudlicky, J. Fluorine Chem., 1981, 18, 385. G. Meazza, L. Capuzzi and P. Piccardi, Synthesis, 1989, 331. T. Umemoto and Y. Gotoh, Bull. Chem. Soc. Jpn., 1986, 59, 439. H.C. Brown, H.L. Gewanter, D.M. White and W.G. Woods, J. Org. Chem., 1960, 25, 634. H.C. Brown, J. Org. Chem., 1957, 22, 1256. J.F. Harris, R.J. Harder and G.N. Sausen, J. Org. Chem., 1960, 25, 633. J.L. Boston, D.W.A. Sharp and G. Wilkinson, J. Chem. Soc., 1962, 3488. J.F. Harris, US Pat. 2 923 746 (1960); Chem. Abstr., 1962, 54, 9799a. H.C. Brown and H.L. Gewanter, J. Org. Chem., 1960, 25, 2071. R.D. Chambers, C.G.P. Jones, M.J. Silvester and D.B. Speight, J. Fluorine Chem., 1984, 25, 47. C.G. Krespan, Tetrahedron, 1967, 23, 4243. R.D. Chambers, W.K.R. Musgrave and S. Partington, Chem. Commun., 1970, 1050. W.T. Flowers, R.N. Haszeldine and P.G. Marshall, Chem. Commun., 1970, 371. R.D. Chambers and C.G.P. Jones, J. Fluorine Chem., 1981, 17, 581. W.T. Miller, R. Hummel and L.F. Pelosi, J. Am. Chem. Soc., 1973, 95, 6850. R.D. Chambers, S. Partington and D.B. Speight, J. Chem. Soc., Perkin Trans. 1, 1974, 2673. R.D. Chambers, S. Nishimura and G. Sandford, J. Fluorine Chem., 1998, 91, 63. R.W. Kaesler and E. LeGoff, J. Org. Chem., 1982, 47, 4779. N.P. Stepanova, N.A. Orlova, V.A. Galishov, E.S. Turbanova and A.A. Petrov, Zh. Org. Khim., 1985, 51, 979. C.G. Krespan, B.C. McKusick and T.L. Cairns, J. Am. Chem. Soc., 1961, 83, 3428. R.D. Chambers, A.J. Roche and M.H. Rock, J. Chem. Soc., Perkin Trans. 1, 1996, 1095. W.J. Feast in Fluorine Chemistry at the Millennium, ed. R.E. Banks, Elsevier, Amsterdam, 2000, p. 142. R.D. Chambers and A.R. Edwards, Tetrahedron, 1998, 54, 4949. W. Mahler, J. Am. Chem. Soc., 1962, 84, 4600. W.R. Cullen and M.C. Waldman, Inorg. Nucl. Chem. Lett., 1968, 4, 205. B. Verkoczy, A.G. Sherwood, I. Safarik and O. Strausz, Can. J. Chem., 1983, 61, 2268. C.G. Krespan, J. Am. Chem. Soc., 1961, 83, 3434. R.D. Chambers, C.G.P. Jones and M.J. Silvester, J. Fluorine Chem., 1986, 32, 309. R. Fields, R.N. Haszeldine and I. Kumadaki, J. Chem. Soc., Perkin Trans. 1, 1982, 2221.

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Chapter 8

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

This chapter contains only a brief survey of the chemistry of a range of derivatives that are of interest to the organic chemist; further aspects have been discussed in detail and may be referred to elsewhere [1, 2]. Because of the extreme electronegativity of fluorine and fluorocarbon groups, the acidities of various functions are increased by introduction of these groups. Some examples are given in Table 8.1: it is clear that fluorocarbon groups have a dramatic effect on the acidities of alcohols and carboxylic acids. Moreover, the CF3 SO2 group is one of the most electron-withdrawing groups known [3] and consequently the carbon acid ðCF3 SO2 Þ2 CH2 is more acidic than trifluoroacetic acid. Also, the sulphonamide ðCF3 SO2 Þ2 NH is a strong acid [4]. Conversely, fluorine or fluorocarbon groups have a major effect in reducing the base strength of amines, ethers and carbonyl compounds; for example, 2,2,2-trifluoroethylamine (pKb ¼ 3:3) is ca. 105 times less basic than ethylamine. Also, pentafluoropyridine is only protonated in strong acid [6], whereas hexafluoroacetone is not protonated even in superacids [7–9] and perfluorinated tertiary amines and ethers are sufficiently non-basic for them to be used as inert fluids interchangeably with perfluorocarbons.

I OXYGEN DERIVATIVES A Carboxylic acids 1 Synthesis The electrochemical fluorination process [10] (see Chapter 2, Section IVA) is particularly effective for the synthesis of polyfluoroalkanoic acids and is applied on an industrial Table 8.1 Acidities of fluorinated systems [3, 5]

236

Acid

pKa

CH3 COOH CF3 COOH ðCH3 Þ2 CHOH ðCF3 Þ2 CHOH ðCF3 Þ3 COH ðCF3 SO2 Þ2 CH2 ðCF3 SO2 Þ2 NH

4.76 0.52 16.1 9.3 5.4
1.0 1.7

Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

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237

scale, although hydrolysis of chlorofluoroalkanes can also be a useful process [11, 12]. Dicarboxylic acids may be obtained by oxidation of cyclic alkenes; examples are shown in Table 8.2. Table 8.2 Preparation of fluorinated carboxylic acids Reaction

Ref. ECF

RCOCl

RFCOF

H2O

RFCOOH

[13]

e.g. RF = CF3, C4F9 i

CF3CCl3

[14]

CF3COOH

i, SO3, BF3 i

C8F17I

C7F15COF 83%

[15]

i, Fuming H2SO4, PCl5 i, ii

CF2=CF2

i, K2S2O8, FeSO4, H2O ii, Esterification i

CF3(CF2)6I(Br)

[16]

(CF2)n(COOMe)2 n = 1−11

CF3(CF2)5COONa 83%

[17]

i, HOCH2SO2Na, NaHCO3, DMF, H2O, 90
C i

(CF2)4(CH2CH2OH)2

(CF2)4(CH2COOH)2 69−95%

[18]

i, CrO3−H2SO4 i H(CF2)6CH2OH

H(CF2)6COOH

[19]

i, HNO3, FeCl2.nH2O

CHF2COF

hν

+ Br2

i

CF2ClCFClCCl3

65%

BrCF2COF

[20]

CF2ClCFClCOOCl ii

[21] CF2ClCFClCOOCD3

iii

CF2=CFCOOCD3

i, Oleum ii, CD3OD iii, Zn

Contd

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238

Chapter 8

Table 8.2 Contd Reaction

Ref. X SbF5

Cl

i

F

(CF2)4(COOH)2 X

i, Alk. KMnO4

X = Cl, F Cl

Cl

i Cl

ii

F O

O

[22, 23]

i, SbF3.SbCl5.

O(CF2COOH)2

[24]

ii, KMnO4

2 Properties and derivatives Boiling points of perfluoroalkanoic acids are lower than for corresponding alkanoic acids, which indicates a significant reduction in intermolecular forces for the fluorocarbon acids. They are very strong in comparison with other organic acids (see Chapter 4, Section IIIA, Subsection 1) and, correspondingly, most of the metal salts, e.g. those of trifluoroacetic acid, are water- and alcohol-soluble whilst the silver salts are soluble in ether and benzene. Alkali-metal salts of higher acids are used as emulsifying agents. A range of normal functional-group chemistry may be carried out with perfluoroalkanoic acids, little modified by the perfluoroalkyl group [2, 25, 26]. Acid chlorides are readily obtained with thionyl chloride or phosphorus chlorides and may be converted to the fluorides using potassium fluoride or, where a volatile product is obtained, by exchange with benzoyl fluoride (see Chapter 3, Section IIB); anhydrides are produced by reaction of the acid with phosphorus pentoxide [27]. To illustrate some of the chemistry of perfluoroalkanoic acids, a selection of reactions is contained in Table 8.3. Table 8.3 Reactions of perfluoroalkanoic acids and derivatives Reaction

Ref.

OH

CF3

O O

OH

[28]

i

O

O

i, CF3COOH

Contd

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239

Table 8.3 Contd Reaction

Ref.

CF3COOH + C6H5COX

CF3COX + C6H5COOH

[29]

X = Cl, F

CF3COONa + POCl3

i

[30]

90%

CF3COCl

i, 100
C, 24 h CF3COOH + P2O5

[27]

(CF3CO)2O i

CF3COOC2H5 + NH3

[31]

99%

CF3CONH2 i, (C2H5)2O, 0
C

i

C2F5CONH2

C2F5Br

[32] i, Br2, NaOH i CF3COOC2H5 + NH3

99%

CF3CONH2

[33]

i, (C2H5)2O, 0
C i CF3COOC4H9 + LiAlH4

76%

CF3CH2OH

[34]

i, (C2H5)2O, Reflux i CF3COCl

CF3COCHN2

ii

CF3CH2COOC2H5

62%

40%

[35]

i, CH2N2, 0−20
C; ii, Ag2O, C2H5OH i CF3CONH2

CF3CN

74%

[31]

i, P2O5, 150−200
C

Pyrolysis of alkali-metal salts does not lead to simple decarboxylation but, instead, elimination of fluoride also occurs; this is a useful synthetic method [36], commercialised in the synthesis of monomer for the manufacture of Nafiont [37] (Figure 8.1); see Chapter 7, Section IIB for the preparation of fluoroalkenes. Decomposition of sodium salts of dicarboxylic acids is more complicated [38] (Figure 8.2).

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240

Chapter 8

CF2=CF2

SO3

F2C

CF2

O

SO2

F FCOCF2SO2F

½37

F OCF2CF(CF3)OCF2CF2SO2F

HFPO

OCF2CF2SO2F

HFPO Na2CO3

FCO[CF(CF3)OCF2]2CF2SO2F

Heat CF2=CFOCF2CF(CF3)OCF2CF2SO2F

HFPO =

CF2

CF3CF

CF2=CF2

O

Co-polymer

Figure 8.1

(CF2)4(COONa)2

i

CF2=CF(CF2)2COONa

i, 460
C, 10

−2mm

ii

(CF2=CF-)2

ii, 160−450
C, 10−2mm

½38

61%

Figure 8.2

The Hunsdiecker method has been applied effectively for the replacement of carboxyl by bromine and iodine [39–42] (Figure 8.3) but on an industrial scale the products are more effectively obtained by other processes [43]. Routes starting from alkenes are particularly significant (Figure 8.4). It is important to note that the toxicities of these iodoalkanes appear to be increased dramatically from that of trifluoroiodomethane, which is relatively harmless (and has unwisely been considered as a fire-extinguishing agent), to those of the tertiary iodides, which are dangerously toxic [44]. CF3CO2Na

AgNO3

CF3CO2Ag

I2 Heat

CF3I

91%

½40

Figure 8.3

The particular toxicity of perfluoro-t-butyl iodide is most probably related to the efficiency of the iodide as a one-electron acceptor in reactions with nucleophilic sites in the body.

3 Trifluoroacetic acid The advantages of trifluoroacetic acid as a very strong organic acid have, of course, been appreciated for a long time; they include its unusual properties as a solvent for kinetic

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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives IF5/I2

CF2=CF2

CF2=CFCF3

IF5/I2

½45, 46

86%

½45, 46

99%

(CF3)2CFI i

CF2=CFCF3

F

C2F5I

241

(CF3)2CFI

61%

½47

(CF3)3CFI

61%

½48

i, KF, I2, CH3CN, 100
C CF2=C(CF3)2

F

i

i, KF, I2, CH3CN, 130
C

Figure 8.4

studies, e.g. for electrophilic aromatic substitution reactions [49] or solvolysis studies [50]. The acid is a good ionising medium but appears to have a surprisingly low solvating effect, or nucleophilicity, towards cations, apparently because of the high internal stabilisation of the CF3 COO
ion. Conversely, the medium is highly efficient in solvating anions through hydrogen bonding. As a consequence of these effects, trifluoroacetic acid provides a useful medium for solvolytic reactions of pronounced SN 1 character because this allows inductive and anchimeric assistance effects to play a more important part in carbocation generation than is observed using more nucleophilic solvents [50]. The acid may be used as a solvent for promoting the formation of strong electrophiles, e.g. for nitration. Trifluoroacetamide has been used in an alternative procedure to the Gabriel synthesis for amines [51] (Figure 8.5). RX

+

NaNHCOCF3

RNHCOCF3

e.g. RX = n-C8H17I,

NaBH4

RNH2

½51

Yield = 79%

Figure 8.5

The field of fluorinated amino acids and peptides is already established and recent developments are important to both chemistry and biology. The reader is directed to an excellent entry volume [52] and reviews [53].

4

Perfluoroacetic anhydride

The utility of perfluoroacetic anhydride as a medium for promoting esterifications is well known [54] and, again, is based on the stability of the trifluoroacetate ion (Figure 8.6). RCOOH

+

R'OH

+

(CF3CO)2O

½54 RCOOR'

Figure 8.6

+

2 CF3COOH

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It is probable that on addition of a carboxylic acid to the alcohol/anhydride mixture trifluoroacetic acid is formed, together with a mixed anhydride that is either highly polar or actually ionised to give an acylium ion in solution (Figure 8.7). RCOOH

+

(CF3CO)2O

CF3COOH

+

CF3CO.OCOR

−

CF3COO

+

+

RCO

Figure 8.7

Esterification of a wide range of compounds has been achieved, often under very mild conditions. Trifluoroacetates are also formed readily using perfluoroacetic anhydride and are subsequently easily hydrolysed; consequently the trifluoroacetate group finds common usage in carbohydrate and peptide chemistry [54] for blocking OH and NH2 groups. The anhydride has been used to form N-(trifluoroacetyl)succinimide, which is claimed to be a convenient trifluoromethylating agent [55].

5 Peroxytrifluoroacetic acid The uses of this reagent were developed by Emmons. It is prepared by mixing the anhydride with 90–95% hydrogen peroxide [56] (Figure 8.8); although a mixture of hydrogen peroxide and trifluoroacetic acid is sometimes used, it is less effective. It is claimed that the use of sodium percarbonate and the anhydride is also an effective methodology [57].

(CF3CO)2O

+

H2O2

CF3COOH

CF3

C

δ− O

δ+ OH

½56

O

Figure 8.8

Peroxytrifluoroacetic acid is a powerful peroxy-acid and only the expense of the reagent inhibits its more widespread use. It will efficiently bring about the oxidations for which peracids are normally used, such as the Baeyer–Villiger oxidation of ketones to esters [58] and the conversion of alkenes to glycols [59] or, when a buffer is present, to epoxides [60] and nitrosamines to nitramines [56, 61]. However, the reagent will also convert aromatic amines to nitro compounds [62], even with amines containing electronwithdrawing substituents [63]. Similarly, oxidation of perfluorodibenzothiophene to the dioxide occurred [64] where other reagents had failed. Peroxytrifluoroacetic acid reacts with aromatic systems by effecting electrophilic hydroxylation [65] leading to phenols, quinones or cyclohexadienone derivatives [65, 66], and the efficiency of the reagent is significantly increased by the addition of boron trifluoride [66] (Figure 8.9).

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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives CF3CO2OH

C6F5NH2

F

C6F5NO2

i

F

243

½63

F

½64

S

S O

i, CF3COOH, H2O2

O

OH H3C

½66

CH3

H3C

CH3 CF3CO2OH

CH3

CH3

O

(CH3)6

CF3CO2OH/BF3

½66 (CH3)6

90%

Figure 8.9

B 1

Aldehydes and ketones Synthesis

Selective fluorination of aldehydes and ketones has been carried out by a variety of electrophilic procedures [67–70] and enantiomerically enriched forms have been achieved in a number of cases. A range of polyfluoroalkyl ketones has been synthesised but, generally, by methods quite distinct from those that would be used to synthesise corresponding hydrocarbon derivatives. Some examples are given in Table 8.4. Hexafluoroacetone [67] and chlorofluoroacetones are commercially available and are made by exchange of chlorine in hexachloroacetone by fluorine, using a Cr(V) or Cr(III) catalyst, and fluoral, CF3 CHO, has also been made on a commercial scale by analogous catalytic processes, starting with chloral, CCl3 CHO [71]. Preparations of trifluoromethyl ketones have been reviewed [72].

2

Reactions [93–96]

The carbonyl group in a perfluorinated ketone is clearly very electron-deficient and this feature dominates the chemistry of these compounds. It is reflected in, for example, the rise in vibrational frequency of the carbonyl group in polyfluoro-ketones [97, 98] from normal values and by the fact that hexafluoroacetone is not protonated in the superacidic FSO3 H=SbF5 mixture [8].

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244

Chapter 8

Table 8.4 Syntheses of perfluorinated aldehydes and ketones Reaction

Ref. i

CF3CHBrCl

CF3CHO

[73]

ii, H2O

i, Oleum, HgO, reflux; i, ii

CF3Br

ii

(CF3CHSO3)

ca. quant.

CF3CH(OCOCH3)2

[74] i, Electrochem. Red'n, DMF, Bu4NBr, Al anode, Lewis acid or Me3SiCl (trace). ii, (CH3CO)2O, HCl, Pyridine i, ii

iii

RF(CF2)nCH(OH)2

RF(CF2)nCOOH

i, LiAlH4; ii, H2SO4; iii, P2O5

[75]

n = 0, 1, 2 F

i

RF(CH2)nCH2OH

CF3(CF2)nCHO

CHO

RF(CH2)nCHO R'F

H

[76]

i, Swern Oxidation or Pyridinium Chlorochromate RF = C4F9, R'F = C3F7, n = 1−4 i

CF2=CFCF3

FCO(CF2)3COF

(CF3)2CFCO(CF2)3COCF(CF3)2 75% Conversion

i, CH3CN, KHF2, 120−125
C SbF5

CF3CF2CF=C(OMe)CF3

[77]

CF3CF=CFCOCF3

[78]

i, ii FCO(CF2)nCOF

CF3CO(CF2)nCOCF3

Me3SiCF3

n = 2,3

[79]

(ca. 90%)

i, KF; ii, Heat, Vacuum

(C2H5O)2CO

(n-C3F7)2C(OH)2

P2O5

(n-C3F7)2CO

[80]

88% CF3CCl=CClCF3

i

CF3COCOCF3 31%

[81]

i, CrO3, fum. H2SO4, 60−70
C, 1.5 h

Contd

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245

Table 8.4 Contd Reaction

Ref.

F3C

F

F

F

Cr2O3 or Al2O3

[82, 83]

(CF3)2CO

O i

O

F

F

O

[84] i, CsF, Pt, 150−300
C, 1.5h, 300
C, 2h OCH3 CF2=CF2

CF2=CFOCH3

175
C

F

H2SO4

[85]

OH

O

P2O5

OH

F

F

Heat F

OCH3

F OCH3

(CF2)n

CoF3

(CF2)n

OCH3 (CF2)n F

F

F

F

[86, 87]

H2SO4 O

OH P2O5

OH (CF2)n

(CF2)n

F

F F

F

CF2=C(CF3)2

P2O5

H2O

(CF3)2CHCOOH

THF

(CF3)2C=C=O

[88]

77% OH RF

C

OH CF=CF2

Br2

RF

H

C

CFBrCF2Br

H Na2Cr2O7.2H2O H2SO4 Zn/Dioxane

RFCOCFBrCF2Br

[89]

RFCOCF=CF2 RF = CF3; C2F5

Contd

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Chapter 8

Table 8.4 Contd Reaction F F

C

Ref. O C

F C F3C OH

O

CF2

i

Na

CF2HCOCF3

C OH

F3C

[90]

45%

i, Nitrobenzene, 200
C i, ii

C6F13(CH2)2I

RFCO(CH2)2C6F13

i, t-BuLi, −78
C ii, RFCO2Et, −78
C

RFCOCl + (i-Pr)3SiH

[91]

RF = CF3 (89%) RF = C7F15 (68%) i

RFCHO + (i-Pr)3SiCl

i, Pd/C, 25 to 30
C

RF = C7F15 RF = n-C3F7

[92]

90% 60%

Addition to C5O: Synthesis of homochiral systems is an important aim [99, 100] and the steric requirements of hexafluoroacetone may lead to quite different stereochemical outcomes from other carbonyl systems [101] (Figure 8.10). H CH3

i X

CO

CH2CH3

ii X

X Et2BO

Re

i, Et2BOTf, i-Pr2NEt, −5
C, 30min. ii, (CF3)2CO, −78 to 5
C

CF3 OH

O

½101

CF3

X = N SO2

Figure 8.10

Because of the ready reaction of fluorinated ketones with nucleophiles there is a considerable literature on this subject, although it is dominated by that of hexafluoroacetone. Burger and co-workers have prepared a variety of heterodienes, 8.11A (Figure 8.11), from hexafluoroacetone and developed an extensive chemistry of these derivatives, especially the formation of heterocycles [95, 96]. A significant feature in this chemistry is the presence of low-lying HOMOs in the heterodienes; this has made possible a range of cycloaddition reactions [95, 96]

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247

C(CF3)2 Y

X = O, S, NR2

½95, 96

Y = N, CH R1

X 8.11A C(CF3)2

C(CF3)2OH NH2

HN

i

e.g. (CF3)2CO R1

NR2

R1

N R1

NR2

NR2 80−90%

i, POCl3, Pyridine F3C CN

i

N

(CF3)2CO R1

CF3

NH

O

R1

NH 75−84%

i, Et2O, −30
C - room temp.

R1 = CH3, CH(CH3)2

Figure 8.11

(Figure 8.12). The heterodienes are useful traps for a variety of reactive intermediates and they are good one-electron acceptors. For example, reaction with SnCl2 leads to defluorination and cyclisation [95] (Figure 8.13). F3C

C(CF3)2 N C R1

NR2

½95, 96

NR2

N

i

NR3

CF3

NR3

R1 77−93%

i, Toluene, 50−70
C, 24−36 hr.

Figure 8.12 F3C N

N

R

F 1

X

R

½95

N

−F

SnCl2 1

F3C

C=CF2

C(CF3)2

X

R1

X SnCl2F2

X = O, S, NR2

Figure 8.13

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Chapter 8

Hexafluoroacetone reacts with amino acids to give heterocyclic systems (Figure 8.14) which are highly volatile and may be used for GLC analysis. They also show potential for synthesis of natural and unnatural amino acids [96, 102]. O

½96, 102

HOOC HN F3C

O CF3

Figure 8.14

Addition of amino compounds to hexafluoroacetone occurs very readily indeed, but subsequent dehydration to form, for example, oximes or semicarbazones from the corresponding adducts does not normally occur. Special procedures usually have to be employed, the most effective being elimination of amines from adducts to form imines that are derived from the ketone, as illustrated in Figure 8.15. NHNHCONH2 (CF3)2C=NPh + H2NNHCONH2

(CF3)2C

½103, 104

NHPh

∆ or HCl (− PhNH2) (CF3)2C=NNHCONH2

Figure 8.15

Haloform-type cleavage of fluoro-ketones occurs in the presence of excess base but intermediate metal salts of the gem-diols can be isolated in some cases [105] (Figure 8.16). OH

RF MOH

+

(RF)2CO

C RF OM

RFCOOM

+

RFH

½105

Figure 8.16

Reaction of hexafluoroacetone with water occurs exothermically to give a stable solid gem-diol that is acidic (pKa ¼ 6:58) [94], or a liquid sesquihydrate; an adduct is formed with hydrogen peroxide that functions as a peroxy-acid [106] and, on thermal decomposition, gives the interesting peroxide CF3 OOH [93, 107]. Reaction of CF3 COCH3 with 30% hydrogen peroxide gave a stable tetroxane [108] (Figure 8.17). In recent developments, the hydrogen peroxide is generated in situ, in a catalytic process using N-hydroxyphthalimide and oxygen, in the presence of hexafluoroacetone or its hydrate. The system is useful for epoxidation of alkenes, which occurs in a regio- and stereoselective manner [109]. Also, the use of Oxonet (KHSO5  KHSO4  K2 SO4 ) with CF3 COC6 H13 , in aqueous ðCF3 Þ2 CHOH as solvent, has been developed [91]. Oxonet

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249

in combination with ðCF3 Þ2 CO is a very powerful oxidant, proceeding by the intermediate formation of the corresponding dioxirane [110] (Figure 8.18). Catalytic diastereoselective epoxidation of chiral allylic alcohols, using hexafluoroacetone hydrates, has also been reported [111]. Some additions are shown in Figure 8.19.

CF3COCH3

+

H2O2

F3C

CH3

O

O

O

O

½108

CH3

F3C

Figure 8.17

O

F3C CF3COCF3

C F3C

Oxidation reactions

½110

O

Figure 8.18

CF3COCF3

CF3COCF3

H2O

H2O2

(CF3)2C(OH)2

(CF3)2C(OH)OOH

½112

½106, 107

∆ CF3COOH

CF3COCF3

H2S

(CF3)2C(OH)SH

½113

Figure 8.19

Even though protonation of hexafluoroacetone has not been observed, reaction with aromatic compounds may be achieved in the presence of Lewis acids, suggesting at least some degree of co-ordination of the Lewis acid [93]. The orientation of substitution depends on the catalyst but, using weaker systems, e.g. boron trifluoride or hydrogen fluoride, the cross-linking agent bisphenol AF is obtained (Figure 8.20). Wittig reagents, including apparently even the normally unreactive derivatives, give the corresponding alkene derivative on reaction with hexafluoroacetone [114], as for example in Figure 8.21. Unusually, intermediates may be isolated; these may then be converted to the alkene by gentle heating [115, 116].

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250

Chapter 8 OH i

CF3COCF3

C(CF3)2

HO

OH

½93

i, BF3, or HF

Figure 8.20 (CF3)2C=CHCOCH3

CF3COCF3 + (C6H5)3P=CHCOCH3

½114

Figure 8.21

Some unusual reactions can occur between fluorinated ketones and trialkylphosphines [117] or trialkylphosphites [118] (Figure 8.22). C6H5 C6H5COCF3

+

(n-C4H9)3P

H C

F3C

(C2F5)2CO

+

½117

C (CH2)2CH3

C2F5C(OC2H5)=CFCF3

P(OC2H5)3

+

½118

FPO(C2H5)2

Figure 8.22

Uncatalysed reactions with alkenes or alkynes will occur and cycloaddition products may be obtained (Figure 8.23). (C2F5)2CO + CH2=C(CH3)C(CH3)=CH2

100−200
C

C2F5

H3C O

C2F5

½119

H3C

CH2

O F

CH2=CH

CH=CH2

F

CH=CH2

½85

OH

Figure 8.23

Carbonyl groups are normally resistant to radical attack but fluorinated ketones appear to be exceptional in that an extensive free-radical chemistry is possible [93] (Figure 8.24). Copolymers are obtained by free-radical copolymerisation of hexafluoroacetone with, for example, alkenes, tetrafluoroethene and epoxides. Highly fluorinated ketones show some unusual keto–enol phenomena [122]. Remarkably, the pair 8.25A and 8.25B in Figure 8.25 cannot be equilibrated by acid or base; the enol 8.25A, for example, can be distilled from concentrated sulphuric acid. In the presence of base, aldol condensation occurs faster than equilibration.

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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives hν (CF3)2CO

+

½120

(CF3)2CHOSiCl3

CCl3SiH

251

C(CF3)2OH

OC(CF3)2H

½121

hν

(CF3)2CO

C(CF3)2OH C(CF3)2OH

(CF3)2CO

+

(CH3)2CHOH

hν

(CF3)2COH

(CF3)2CHOH

½93 2

Figure 8.24

2 CF2=C(OH)CF3

Base CF2

8.25A

C

½122

CF3

O 8.25C

Slow

8.25B

8.25C CF2HCOCF3

CF3COCF2C(CF3)(CF2H)OH

Fast

8.25B

Figure 8.25

Clearly, the tautomerism is inhibited by a kinetic barrier and this could be the relative instability of the anion 8.25C, where electron-pair repulsion involving non-bonding pairs on fluorine could be significant. Enols of cyclic systems are also unusually stable [123] and the equilibrium constant depends on the solvent (Figure 8.26). OCH2Ph F

F

OH F

½123

Stable in THF

Figure 8.26

Reactions with fluoride ion: With the exception of CF3 OH (see the next section), fluorinated alcohols of the type RF CF2 OH are not known [124] but complexes of K, Rb, Cs, Ag or ðC2 H5 Þ4 Nþ fluorides with hexafluoroacetone have been isolated [125, 126], following from the earlier isolation of some similar complexes with carbonyl fluoride [127]. These complexes have been reasonably formulated as fluorinated alkoxides (Figure 8.27), but the use of these salts in synthesis is often difficult because the complexes may also act as fluoride-ion donors [128].

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252

Chapter 8 MF + (CF3)2CO

(CF3)2CFOM

Figure 8.27

More stable complexes have been obtained by using ‘TAS’ fluoride [129], and X-ray data on the salt (8.28A) are quite revealing (Figure 8.28). Carbon–fluorine bonds are exceptionally long in CF3 O
while the C–O distance is quite short; these observations have been advanced as evidence for negative hyperconjugation (Chapter 4, Section IIIB) (Figure 8.29). COF2

+

−

+

(Me2N)3S Me3SiF2

THF −75
C

−

CF3O

(Me2N)3S

+

½129

8.28A

'TAS' fluoride

Figure 8.28 −

−

CF3 O

F

CF2=O

Figure 8.29

Other stable alkoxide salts have been prepared [130] using hexamethylpiperidinium fluoride, and X-ray structural data for these systems are also consistent with negative hyperconjugation (Figure 8.30).

−

(CF3)2C=O

(CF3)2CF

F

N

½130

−

O

N

Figure 8.30

Reaction of a mixture containing hexafluoroacetone and caesium fluoride with allyl bromide or chloride occurs readily [131, 132] (Figure 8.31) but the mixture does not react with trimethylchlorosilane [131]. (CF3)2CO

+

CH2=CHCH2Br

i

CH2=CHCH2OCF(CF3)2

½131, 132

i, CsF, Diglyme, 55
C, 12hr

Figure 8.31

Difficulties undoubtedly arise because perfluorinated alkoxides are very weak nucleophiles but they are also potentially fluoride-ion donors and therefore, at the temperatures necessary for reaction, the alkoxides are probably significantly dissociated and consequently undergo competing side-reactions. Perfluoro-esters RF CO2 R1F have been made [133] in reactions using ðRF Þ2 CFOM carried out at low temperatures, with the products being isolated before they are allowed to warm up. Otherwise, fluoride ion attacks the ester itself, giving the reverse reactions, because (it must be remembered) the corresponding alkoxide ion RF O
will be quite a good leaving group in a nucleophilic displacement process (Figure 8.32).

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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives (CF3)2CO + MF

RFCOF

−

RFCO2CF(CF3)2 + F

253

½133

−78
C

Figure 8.32

Likewise, perfluoroalkoxytriazines may be isolated at low temperatures [134] (Figure 8.33). RF

N (CF3)2CO

N

RF

N

½134

KF

Cl

N

N

N RF

RF = OCF(CF3)2

Figure 8.33

Perfluoroalkoxyanions are also generated by reaction of fluoride ion with acid fluorides and with epoxides (see Section IIIB, below). Reaction of the ðCF3 Þ2 CO
CsF complex with tetrafluoroethene [135] gives alkoxide 8.34A, not a carbanion 8.34B (Figure 8.34). In the presence of iodine, however, ethers are formed [126], indicating the formation of intermediate hypoiodites, RF OI (Figure 8.35). −

CF2=CF2 + F

+ (CF3)2CO

−

½135

(CF3)2CFO

CF3CF2

(CF3)2CO

−

CF3CF2C(CF3)2O 8.34A

CF2=CF2

(CF3)2CFOCF2CF2

etc

8.34B

Figure 8.34

CF2=CF2 + (CF3)2CO + KF + I2

(CF3)2CFOCF2CF2I

½126

ca. 98% yield 17% conversion

Figure 8.35

A hypochlorite has been obtained by reaction of ðCF3 Þ3 COH with ClF at low temperature [136]. In an analogous way, hypofluorites may be formed by reactions of intermediate perfluoroalkoxide ions with elemental fluorine; this chemistry is being exploited in industry for the manufacture of important monomers [137] (Figure 8.36).

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Chapter 8

CO

i, ii

iii

CF3OF

i, ii

CF3CF2CF2OF

CF3OCFClCF2Cl

∆

CF3CF2CF=O

½137

CF3OCF=CF2

iii C3F7OCF=CF2

C3F7OCFClCF2Cl

i, F2 ii, MF (M = K, Rb, Cs), −78
C iii, CFCl=CFCl

Figure 8.36

It appears that hypofluorite formation occurs by nucleophilic attack via the very weakly nucleophilic perfluoroalkoxide ions on elemental fluorine, regenerating fluoride ion, because the process is catalytic in alkali-metal fluoride (Figure 8.37). F + RFCF=O

RFCF2O +

F

F

RFCF2OF + F

Figure 8.37

Hypofluorites are also formed by similar catalytic formation of perfluoroalkoxide ions from the corresponding oxiranes (Figure 8.38). O CF3CF

CF2

F

F2

CF3CF2CF2OF

F

½137

Figure 8.38

The chemistry of fluorinated 1,3-diketones has been reviewed [138].

C Perfluoro-alcohols 1 Monohydric alcohols The 2CF2 OH system is thermodynamically unstable, by an estimated 80
160 kJmol
1 , with respect to formation of C5O and hydrogen fluoride. Nevertheless, a remarkable low-temperature synthesis of trifluoromethanol [139] led to a system that is sufficiently kinetically stable at low temperatures to be characterised, and a gas-phase IR spectrum has been obtained (Figure 8.39). CF3OCl + HCl

Figure 8.39

−120
C

CF3OH + Cl2

½139

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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

255

The driving force for forming C5O via elimination of hydrogen fluoride is much reduced in strained systems, and therefore the alcohols in Figure 8.40 are more stable [140]. Systems of the form RF CH2 OH are, however, quite stable and are extremely useful solvents [141] because of their high polarity [142]. OH

O HX

½140

X X = F, Cl, Br, I

Figure 8.40

Perfluoro-t-alcohols are quite stable and are very strongly acidic; for example, compare ðCF3 Þ3 OH and ðCH3 Þ3 OH which have pKa values of 5.4 and 19.0 respectively [143, 144]); see Chapter 4, Section IIA. Perfluoro-t-butanol is obtained most easily from hexafluoroacetone when it is heated with caesium fluoride in diglyme containing traces of moisture [145] (Figure 8.41). The first stage involves a carbanion transfer and can be formulated in a manner similar to the benzil–benzilic acid rearrangement although it occurs, in this case, by an intermolecular process (Figure 8.42). i (CF3)2CO

ii

CF3COF + (CF3)3COCs

(CF3)3COH 34%

i, CsF, 150
C, Diglyme.

½145

ii, H2SO4

Figure 8.41

(CF3)2CO

CsF CF3

δ+ δ − Cs O

O

CF

C

CF3

δ+ Cs CF3

CF3

O

δ− O

CF

C(CF3)3

CF3

Figure 8.42

Some other routes to fluorinated alcohols are shown in Figure 8.43a. Trifluoroethanol has become a much-used ‘building-block’ [150] for a wide range of synthetic procedures (see also Chapter 6, Section II) (Figure 8.43b), and sigmatropic rearrangements have been exploited to move the fluorine labels to ‘internal’ sites [151].

2

Dihydric alcohols

Perfluorinated ketones form stable hydrates, ðRF Þ2 CðOHÞ2 , and these diols are very acidic. Hexafluoroacetone hydrate is known to be a very good solvent and is particularly useful for certain polymers [112, 152]. Perfluoropinacol may be obtained from hexafluoroacetone by photolytic reduction (Figure 8.44), whilst classical reduction with magnesium amalgam gives only low yields [112]. The same pinacol is also obtained by heating 8.44A, which is produced as shown in Figure 8.44 [153].

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Chapter 8

i, ii

CCl3Li + (CF3)2CO

iii

(CF3)2C(CCl3)OH

(CF3)3OH

50%

60%

½146

i, THF, −100
C ii, H2SO4 iii, SbF5

i

CF3CH2Cl + H2O

CF3CH2OH

½147

i, 400−500
C, Catalyst

hν

CH3OH + CF2=CF2

HCF2CH2OH

½148

O (CF3)2C

CH2

HX

XCH2C(CF3)2OH

½149

X = FSO2O, CF3SO2O, Cl, I

Figure 8.43a i

CF3CH2OTs

OTs

OTs

ii

CF2=C

CF2=C

Li i, n-BuLi ii, R3B iii, CuI, HMPA

½150

Li BR3 1,2 shift

OTs CF2=C

R

iii

CF2=C BR2

Cu

i, ii

F

OMEM

CF3CH2OMEM F

iii

F

OMEM

F OH

O

MEM = CH2OCH2CH2OCH3

F F O

OMEM

OMEM F O

i, LDA, THF, −78
C; ii, EtCHO; iii, Hg(OAc)2, Ethyl vinyl ether, reflux

Figure 8.43b

½151

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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives (CH3)2CO + (CF3)2C(OH)C(OH)CF3)2

i (CF3)2CO

257

½112 iv

ii CF3

F3C CF3

CF3 O

CF3

F3C iii

CF3

O

O

P

i, ii, iii, iv,

CF3

½153

P

OEt OEt

EtO

O

OH

HO OH

8.44A

(CH3)2CHOH/hν P(OC2H5)3 H2SO4 H2O, Boil

Figure 8.44

Diols may also be used in free-radical additions to fluorinated alkenes [154] (Figure 8.45). OH

HO

RFH

½154 CF3CF=CF2 i, γ rays, rt

OH

i 83% RFH

HO RFH

= CF3CFHCF2

Figure 8.45

3

Alkoxides

The formation of polyfluoroalkoxyanions from perfluoroketones was discussed, along with other addition reactions of perfluoroketones, in Section IB, Subsection 2; similar anions can also be generated from acid fluorides and epoxides (oxiranes), as represented in Figure 8.46. F

+

RFR1FCO

F

+

RFCOF

F

+ RFFC

RFR1FCFO RFCF2O

O

O CFR1F

RFCF2CFR1F

Figure 8.46

Examples of fluoride-ion-initiated reactions involving perfluorinated epoxides are shown in Figure 8.47 [155–158]. Hexafluoropropene oxide (HFPO) and tetrafluoroethene oxide will polymerise under certain conditions in the presence of fluoride ion. The process involves an extending alkoxide and it is terminated by elimination of fluoride ion to give

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Chapter 8

an acid fluoride. This reactive end-group may be converted by a variety of procedures [156] into the well-known stable fluids Krytoxt and Fomblint [159]. O F2C CF2

F

CF3COF

[CF3CF2O ]

C2F5O(CF2CF2O)nCF2COF

½155

(R4NF)

CF2CF2

F

[CF3CF2]

(CF3)2CO

CF3 CF3CF2C

½155, 156 O

CF3 HFPO

CF3CF2C(CF3)2OCF(CF3)COF

O

[CF3CF2C(CF3)2OCF(CF3)CF2O]

i

F3CFC CF2 HFPO

(CF3CF2CF2O)

i, MF, Tetraglyme

−F

½158

CF3CF2COF

HFPO

CF3CF2CF2O[CF(CF3)CF2O]nCF(CF3)COF n = 1−4

Figure 8.47

D Fluoroxy compounds [137] An interesting series of compounds RF OF [160, 161] has been synthesised and found to be reasonably stable; for example, the O2F bond energy in CF3 OF has been calculated to be 183 kJmol
1 [162]. Compounds containing more than one fluoroxy group may be obtained but these can be very unstable [163, 164]; indeed, all fluoroxy compounds should be treated with caution. Fluoroxy derivatives of hydrocarbons are less stable, probably due to easy elimination of hydrogen fluoride from these systems. Some syntheses of fluoroxy derivatives are given in Figure 8.48. Fluoroxy compounds are very strong oxidising agents [169]; this may be attributed to the ‘positive halogen’ character of fluorine in an O2F group. Such an approach [170–172] led to the application of CF3 OF as a selective electrophilic fluorinating agent, but the hazards associated with this system have precluded its development as a laboratory reagent. For example, the system is prone to explosive reaction with organic reagents. In fact, a complex interplay of radical and polar intermediates has been indicated for reactions of hypofluorites with electron-rich alkenes [137]. Some hypofluorites may be susceptible to spontaneous exothermic decomposition (Figure 8.49) but, in spite of this, industry has mastered the application of intermediate

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 259

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives i

CO + F2

F2

(COF2)

259

½165, 166

CF3COF

i, Cu Tube, 350
C

CsF

(CF3)2CO + F2

CsF

CO2 + F2

(CF3)3OH

CH3OH

CF2(OF)2

−78
C

+

+

(CF3)2CFOF

−78
C

−20
C

F2

F2

½167

98%

99%

½168

½169

(CF3)3COF

i

ii [CH3OF]

½170

CF3CFClOCH3

i, CH3CH2CN, −40
C, 1hr ii, CF2=CFCl, −75
C to rt

Figure 8.48

CF2(OF)2

−184
C

CF4

+

O2

∆H0 = −360 kJ mol−1

N2

Figure 8.49

hypofluorites to make new perfluorinated ethers and industrially significant monomers. Indeed, this chemistry illustrates well the view that an essential part of the skill of science is to be able to operate potentially hazardous procedures while ensuring the complete safety of the operators. For example, addition of RF OF to fluorinated alkenes (Figure 8.50) has been exploited for the synthesis of important monomers (Figure 8.51) for copolymerisation (See Figure 8.78, page 269). 2 CF2=CF2 + CF2(OF)2

CF2(OCF2CF3)2

80−90%

½173

Figure 8.50

Additions of CF3 OF to sulphur dioxide and trioxide [165], at high temperatures, and to carbon monoxide [174], on photolysis, have been described (Figure 8.52).

E

Perfluoro-oxiranes (epoxides) [156, 158, 175]

Some reactions of epoxides with fluoride and perfluoroalkoxide ions were referred to in Section IB, Subsection 2 (above), and the importance of polymers of these systems was stressed. There are numerous publications or patents concerning the synthesis of these

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260

Chapter 8 i FSO2CF2COF

i, ii

−

FSO2CF2CF2O

FSO2CF2CF2OF

½137

iii FSO2CF2CF2OCF=CF2 i, CsF;

FSO2CF2CF2OCFClCF2Cl

ii, F2; iii, CFCl=CFCl

Figure 8.51

CF3OF + SO3

CF3OF + CO

½165

CF3OOSO2F + SO2FOOSO2F hν

CF3OCOF

½174

86%

Figure 8.52

compounds [156, 158]. The most general process involves reaction of a fluoroalkene with alkaline hydrogen peroxide at low temperatures [176–178]. This method may be used for oxidising hexafluoropropene and higher fluoroalkenes, as well as for cyclic systems (Figure 8.53), but not for tetrafluoroethene, in which case various procedures involving direct reaction with oxygen have been employed [156, 179, 180] (Figure 8.54). It is useful to note that some of the products of these reactions, especially those involving tetrafluoroethene, may be extremely hazardous [179]. CF3CF=CF2

i

F

O F

CF3

½178

25%

F

i, KOH, H2O/CH3OH, 30%H2O2, −78
C

Figure 8.53

CF2=CF2 + O2 (containing O3)

F

O

F F

F 46%

+

CF2CF2O

n

½181

18%

Figure 8.54

Bleaching powder has proved to be a very effective reagent for various epoxidations [158, 182–184], and lithium t-butyl peroxide has been used as an epoxidising agent [185] with electron-deficient alkenes (Figure 8.55). A very unusual, but efficient, rearrangement of the dioxirane 8.56A to a diether 8.56B occurs on heating, but the mechanism of the process is uncertain [186] (Figure 8.56). An interesting use of trimethylamine as catalyst in combination with m-chloroperbenzoic acid (mCPBA) or iodobenzene has been reported and is effective with alkenes having perfluoroalkyl groups attached to the double bond [187] (Figure 8.57).

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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

261

Cl CF3CF2

CF3

F3C

O

CF3CF2

OCl

CF2CF3

½158, 182
184

CF3

F3C

CF2CF3

Z+E

O

CF3CF2

CF3

F3C

74%

CF2CF3 Z : E = 1:1

F3C

CF3

F3C F

O

F3C i

O

F

F

CF3

F3C

CF3

F3C

CF3 O

O

F3C

CF3

F

O

F

F3C

O

CF3

F

F

F

i, t-BuOOLi, THF, −78
C to rt

½186

CF3

O

F3C

CF3

Figure 8.55 CF3

F

CF3

F3C

O

F

CF3 CF3

i

8.56A

F3C F3C

F

F3C

½186

F

O ii

CF3

F3C i, t-BuOOLi, THF, −78
C to rt ii, Sealed tube, 220
C, 19 days

O F3C

O

F F

8.56B

CF3 96%

Figure 8.56

Fluorinated oxiranes undergo a variety of ring-opening reactions with nucleophiles, the most simple of which is formation of an acid fluoride. In most cases, terminal oxiranes open to give an acid fluoride 8.58B rather than a ketone [156, 158] (Figure 8.58) and this specificity of a ring opening is a puzzling feature; it may well be that, in forming an acid fluoride, the strongest set of carbon–fluorine bonds is produced because the 2CF2 O


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262

Chapter 8 CF3

F

½187

O m-ClC6H4CO3H

Me3N

RF

RF

CF3

F

m-ClC6H4CO2H

Me3N-O

RF

RF RF

= CF(CF3)2

Figure 8.57 O

F3C

O

Nuc

F

F −F

½156, 158

RFCFCF2O

RFCFCF2Nuc F

−

−

−F

RFCFCOF

RFCOCF2Nuc

Nuc

8.58A

8.58B

Figure 8.58

group is isoelectronic with 2CF3 . This would then be consistent with the well-known order of decreasing carbon–fluorine bond strengths in the series 2CF3 > 2CF2 2 > CF2; see Chapter 7, Section IB. Ring-opening oligomerisation of the oxirane derived from hexafluoropropene (see Figure 8.47) forms the basis of the production of Krytoxt fluids (DuPont Co.), with end-group stabilisation by direct fluorination etc. Clearly, achieving high-molecularweight material by this process is not easy. For comparison, oxetanes are oligomerised in an analogous way to give intermediate polyfluoro-polyethers that are then further fluorinated to give perfluoro-polyethers in the process for the production of Demnumt fluids (Daikin Co.) [188] (Figure 8.59). F i

CF2=CF2 + (CH2O)n

F

F

½188

F H H

O

ii

F

CF2CF2CF2O

n

i, HF ii, e.g. CsF iii, F2, 100−120
C

Figure 8.59

F

iii

F

CH2CF2CF2O

n-1

CH2CF2COF

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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

263

Examples of other ring-opening reactions are illustrated in Figure 8.60. O

F

F

F

i

−

+

F

−

−

CF3COF + F

[CF3CF2O]

½179

F i, KF, 80
C, 4hr

F3C

O

F

F

i

½189

97%

(CF3)2CFCOF

F i, (CH3)3N, 100
C, 30hr (CH3)3N

−

F −

(CF3)2CCOF

CF3CFCF2O

+ N(CH3)3

+ N(CH3)3

CH3OH

+

O

F3C

F

½178

[CF3CF(OCH3)COF]

F

F CH3OH CF3CF(OCH3)COOCH3 96%

Figure 8.60

So far, the only case where attack occurs at the CF2 position in hexafluoropropene oxide involves reaction with butyl lithium [156] (Figure 8.61). F3C F

O

F +

C4H9Li

[CF3C(O)CF2C4H9]

½156

F i, BuLi, ii, H+

i, ii CF3C(C4H9)(OH).CF2C4H9

Figure 8.61

Ring opening with a strong protonic acid gives the corresponding alcohol [190] and this is consistent with the idea that an intermediate carbocation, 8.62A, would be more stable than 8.62B, where CF3 groups would certainly raise the energy of an adjacent carbocation centre (Figure 8.62). Conversely, cleavage with a Lewis acid catalyst gives a ketone [191, 192] (Figure 8.63). These are interesting reactions because they involve a 1,2-fluorine shift to a positive centre (Figure 8.64), a process that is, of course, very well known for hydride shifts. The conversion of hexafluoropropene oxide to hexafluoroacetone is probably the

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264

Chapter 8 H F3C

+ (CF3)2CCF2OH

O

+ F

F3C

+ (CF3)2C(OH)CF2

½190

F

8.63B

8.62A

H F3C

O

+ F

250
C +

F3C

(CF3)3COH

HF 64hr

F

Figure 8.62

O

i F

F

O

½191

i, Al2O3, 150−300
C

O

C5F11

F

i C5F11CO.CF3

F

½192

F i, SbF5, 150
C, 18hr

Figure 8.63

Acid

Acid

O

O C

F

C F

Figure 8.64

preferred industrial route to this compound (N.B. The ketone is much more toxic than the epoxide [67].) Carbene formation on pyrolysis of epoxides was discussed earlier: see Chapter 6, Section IIIA.

F Peroxides [193, 194] Some examples of formation of fluorinated peroxides are given in Figure 8.65. It has been demonstrated by labelling studies that, in reactions with caesium trifluoromethoxide, ring-opening occurs by attack at the peroxide bond [197] (Figure 8.66). A direct, but mechanistically obscure, synthesis of trifluoromethyl hydroperoxide has been developed, involving the decomposition of the adduct formed between hexafluoroacetone and hydrogen peroxide [107] (Figure 8.67).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 265

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives AgF2

2 CO + 3 F2 2 (CF3)3COH

+

C3F7COCl

t-BuOOH

+

½194

CF3OOCF3

ClF3

+

(CF3)2C(OLi)2

CsF

½194

(CF3)3COOC(CF3)3

½194

C3F7C(O)OOt-Bu O

FC(O)OF

CF2

O

F

O

F

O

F

F3C

O

F3C

O

+ F2

265

½195

½196

Figure 8.65

13COF 2

F

O

13

CF3O

O

F

13CF OOC(O)F 3

½197

F A −F

13CF OOCF O 3 2

nA

13CF O(OCF O) OC(O)F 3 2 n

n = 1-3

Figure 8.66 (CF3)2C(OH)OOH

CF3OOH + CO2 + O2

½107

Figure 8.67

Also, intermediate peroxides are formed in the oxidation of perfluorinated alkenes, e.g. in the photo-oxidation of perfluoroethene and perfluoropropene for the formation of Fomblint (Ausimont Co.) perfluoro-polyether fluids [198, 199].

II

SULPHUR DERIVATIVES [5, 7, 200, 201]

A

Perfluoroalkanesulphonic acids

Trifluoromethanesulphonic acid is commercially available and is the most readily obtained member of this series by electrochemical fluorination [202–205] (Figure 8.68), since the yields of perfluoroalkanesulphonic acids decrease as the size of the alkyl group increases. The acids are very thermally stable; longer straight-chain derivatives are surface-active [206]. This combination of properties appears to be responsible for the application of

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266

Chapter 8

CH3SO2Cl

Eletrochemical Fluorination

CF3SO2OH

CF3SO2F

87%

½203

Figure 8.68

these systems as the basis for textile treatment leading to grease resistance. However, the discovery of traces of perfluoro-octane sulphonic acid in the blood of workers in the industry has caused the removal of these products from the market. Clearly, the long-term stability of sulphonamides derived from perfluorinated sulphonic acids is not as complete as had previously been believed. Of course, the most outstanding property of perfluoroalkanesulphonic acids is that they are extremely useful strong acids, in the ‘super acid’ range [207, 208]; compare the Hammett acidity functions ðH0 Þ: CF3 SO2 OH (
13.8); FSO3 H (
15.1); FSO3 H=20%SbF5 , ‘Magic Acid’ (
20); and H2 SO4 (
11.1). Furthermore, the extreme electron-withdrawing capacity of the CF3 SO2 group [5, 209] is such that ðCF3 SO2 Þ2 NH is the most acidic amide known [4] and it leads to systems with remarkable C2H acidity, e.g. ðCF3 SO2 Þ2 2CH2 ðpKa ¼
1Þ is more acidic than CF3 CO2 HðpKa ¼ 0:52Þ. Consequently, perfluoroalkanesulphonic acids are outstanding Friedel–Crafts catalysts [208, 210]. Moreover, esters of trifluoromethanesulphonic acid, i.e. ‘triflates’, are super leaving groups in nucleophilic displacement reactions and, as such, are extremely important in both mechanistic and synthetic organic chemistry [208]. Significantly, the first example of generating an aryl cation utilised both a triflate leaving group and the ionising ability of trifluoroethanol as solvent [211] (Figure 8.69). OSO2CF3 X

OCH2CF3 X

X

X

X

X

½211

i

i, 120
C, K2CO3, CF3CH2OH X = SiMe3

Figure 8.69

Moreover, the outstanding leaving-group ability of the nonofluorobutylsulphonyl group, ‘nonaflate’, allows the conversion of hydroxyl to fluorine in some cases using n-C4 F9 SO2 F [212], which itself is obtained by electrochemical fluorination (Figure 8.70). Triflate salts are important catalysts because the anions are poorly co-ordinating [214, 215] (Figure 8.71). i

C4F9SO2F

45%

S O

O

Ph(CH2)3OH

i,

HF, E.C.F. ii

Ph(CH2)3F ii, n-C4F9SO2F

Figure 8.70

½213

79%

½212

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 267

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

i

Me3SiCH2Li

ii

CH2(SO2CF3)2

[(CF3SO2)3CLi]

267

½214

M2O3

i, (CF3SO2)2O, pentane, 0
C ii, t-BuLi (2 equiv), (CF3SO2)2O, −78
C

[(CF3SO2)3C]3 M M = Y, Sc

Figure 8.71

Trifluoromethyltriflate can be made easily but nucleophilic attack does not occur on carbon and therefore the system does not act as a source of ‘electrophilic CF3 ’ [216, 217] (Figure 8.72). Nuc (CF3SO2)2O

i

Nuc-CF3

CF3SO2OCF3

½216

90% i, Cat. SbF4(OSO2CF3)

Figure 8.72

Trifluoromethanesulphonic acid forms a very stable crystalline hydrate [205, 218] and reacts vigorously with alcohols, ethers and ketones. Oxonium salts are formed and further reaction may occur on heating (Figure 8.73). (C2H5)2OH(CF3SO3)

CF3SO2OH + (C2H5)2O Figure 8.73

Perfluoralkanesulphonyl chlorides may be obtained from the corresponding iodides [219] (Figure 8.74), and they will act as a source of perfluoroalkyl radicals under pyrolysis or photolysis, by losing sulphur dioxide [220] (Figure 8.75). i

n-C4F9I

n-C4F9SO2Cl

80%

½219

i, SO2,Cl2,DMF,Ni

Figure 8.74 ∆

CF3SO2Cl

CF3Cl + SO2

½221

∆

CF3

(CH3)3CN=O

RFSO2Cl +

O (CH3)3C

i

CF3

Cl SO2

i, hν, or peroxides

Figure 8.75

RF

N

½220

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268

Chapter 8

Trifluoromethyl radicals may also be generated by electrolysis of salts of trifluoromethanesulphinic acid [222] (Figure 8.76). −1e CF3SO2

K

CF3SO2

½222

+ SO2

CF3

E = 1.05V +1e E = −0.8v SO2 OMe

OMe

OMe CF3

OMe

OMe

OMe CF3

Total yield = ca.47%

Figure 8.76

Sulphur-containing compounds are also obtained from reactions involving fluoroalkenes. Polyfluoro-b-sultones are produced in reactions of fluoroalkenes with freshly distilled sulphur trioxide [223, 224]; these sultones have a varied chemistry, including nucleophilic ring opening to give sulphonic acid derivatives (Figure 8.77) (see also Chapter 7, Section IID). This ring-opening reaction is important in the synthesis of co-monomers for the production of Nafiont-type (DuPont) membranes [37] (Figure 8.78). Resins of this type have allowed membrane cells to displace the illfamed mercury cells for chlor-alkali production. Also, Nafiont resin is a useful strong acid and has been developed for solid-phase catalytic processes [225–227] (Figure 8.79). F CF2=CF2

F

F

+ SO3

F

F

½223

CO2H

½223

F

F

F O

SO2

F

F

F

1, NaOH

F2C

F i

i, F , (C2H5)3N

F

F

F

SO2

Figure 8.77

SO2OH

2, Ion Exchange

F O

61%

SO2

O

O F

CO.FCF2SO2F

SO2 N(C2H5)3

F

(C2H5)3N

½37, 223, 224

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 269

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives FCOCF2SO2F + F

½37

OCF2CF2SO2F

CF3 O F

269

i

i,

F F ii, ∆, Na2CO3

FCOCF(CF3)OCF2CF(CF3)OCF2CF2SO2F

iii, CF2=CF2 iv, Hydrolysis

ii

CF2=CFOCF2CF(CF3)OCF2CF2SO2F iii Co-polymer

iv

Membrane

Figure 8.78 R

R

+

i n-BuONO2

15-98% NO2

i, Nafion H

C6H6

+

CH2=CH2

½225

½226

i C6H5C2H5

i, Nafion H

i RSO3H

½227

RSO2Ar

+ ArH

30-82%

R = alkyl or aryl i, Nafion H, Reflux

Figure 8.79

Salts of polyfluoroalkanesulphonic acids may be obtained directly from fluoroalkenes simply by reaction of aqueous sodium sulphite in an autoclave, in some cases in the presence of benzoyl peroxide [228–230] (Figure 8.80). CF2=CF2

+

NaHSO3

120
C

CF3CF=CF2 + NaHSO3 i, (C6H5COO)2, 120
C

Figure 8.80

i

CHF2CF2SO3Na

CF3CFHCF2SO3Na

½228

64%

½229

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270

Chapter 8

B Sulphides and polysulphides A general method for making perfluoroalkyl sulphides and perfluoroalkyl polysulphides involves heating a perfluoroalkyl iodide with sulphur in a sealed vessel, as illustrated in Figure 8.81. 243
C Sx + (CF3)2CFI

[(CF3)2CF]2S

11%

+ [(CF3)2CF]2S3

+

[(CF3)2CF]2S2

34%

½231

18%

Figure 8.81

Many interesting sulphides have been formed [7, 200, 201] by reactions of sulphur with other iodides or certain di-iodides, or by other procedures [232, 233] (Figure 8.82). CF3SSH

+

CF3SCl

120
C

½232

CF3SSSCF3

Figure 8.82

A series of cyclic sulphides is produced in reactions of fluoroalkenes and fluoroalkynes with sulphur or sulphur halides [234–238]; some examples have been discussed in Chapter 7 (Figure 8.83). S Sx +

CF2=CF2

N2 445
C

S

S F

F S

S

S

S

10%

44% 300
C

½234

10hr S F

56%

S

Figure 8.83

The reaction between tetrafluoroethene and sulphur is activated by iodine, presumably via the intermediate formation of a di-iodide [236] (Figure 8.84). S Sx

+

CF2=CF2

+ I2

F

F

S

S

½236

39%

Figure 8.84

Direct syntheses of fluorocarbon–sulphur compounds from non-fluorinated starting materials are limited, but bis(trifluoromethyl) disulphide may be obtained from carbon

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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

271

disulphide using iodine pentafluoride [239], or from thiophosgene using sodium fluoride [240] (Figure 8.85). CS2

IF5

(CF3)2S2

195
C

(CF3)2S3

76% i

(CF3)2S2

CSCl2

½239

7%

+

½240

CS2

37% i, NaF, Sulpholan, 245
C

Figure 8.85

Fluorination of thiophene and derivatives and of 1,4-dithiane [241] with KCoF4 gives a series of fluorinated derivatives. Chlorine–fluorine exchange in sulphides is also possible in some cases [242] (Figure 8.86). PCl5

CH3SCH3

SbF5

CCl3SCH3

½242

CF3SCH3

Figure 8.86

Base-induced [243] addition of thiols to fluoroalkenes yields polyfluoroalkyl sulphides, which have also been further fluorinated (Figure 8.87). CH3SH + CF2=CFCl

i

ii

CH3SCF2CFClH

CH3SCF=CFCl

½243

90% i, NaOCH3, 5−70
C ii, (CH3)2SO, KOH

Cl2

iii, SbF3/SbF5

iii

CH3SCF2CF3

CH3SCFClCFCl2

Figure 8.87

Reaction of arylmagnesium halides with trifluoromethanesulphenyl chloride, or simply condensation of the latter with aromatic systems, has been exploited successfully [244, 245] (Figure 8.88). NaF Sulpholan

CCl3SCl

PhMgBr

+

PhN(CH3)2

Figure 8.88

CF3SCl

CF3SCl

CF3SCl

Et2O

½240 PhSCF3

½244

52%

p-CF3SC6H4N(CH3)2

58%

½245

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272

Chapter 8

C Sulphur(IV) and sulphur(VI) derivatives Electrochemical fluorination of dialkyl sulphides leads to sulphur(VI) derivatives (see Chapter 2, Section III), and oxidation of sulphur also occurs [246] in cobalt fluoride or direct fluorination reactions (Figure 8.89). Electrochemical (CH3)2S

Fluorination

CoF3

CH3SH

250−275
C F2/N2

CS2

48
C

CF3SF5 + (CF3)2SF4

½247

CF3SF5

CF3SF5

½246

CF3SF3

etc.

½248

Figure 8.89

An effective route to some sulphur(IV) compounds involves fluoride-ion-initiated reactions of a fluoroalkene with sulphur(IV) fluoride [249] (Figure 8.90). Alternatively, similar reactions with sulphuryl fluoride give perfluorodialkylsulphones or perfluoroalkanesulphonyl fluorides [250] (Figure 8.91). CF3CF=CF2

+ SF4

CsF 100
C

(CF3)2CFSF3 + [(CF3)2CF]2SF2

½249

Figure 8.90

CF2=CF2 + SO2F2

CsF

(C2F5)2SO2

83%

½250

100
C

CF3CF=CF2

+ SO2F2

CsF Diglyme, 100
C

(CF3)2CFSO2F etc

Figure 8.91

It has been shown that perfluoroalkylsulphur(II) compounds can be oxidised to corresponding sulphur(IV) and sulphur(VI) compounds [251–254] (Figure 8.92). Free-radical reactions of SF5 Br provide a useful approach to sulphur(VI) compounds [256] (Figure 8.93).

D Thiocarbonyl compounds The most simple member of this class of compounds is thiocarbonyl fluoride [257, 258], which is obtained from the thiophosgene dimer 8.94A, and then pyrolysis of 8.94B, to the corresponding fluoro monomer [233] (Figure 8.94).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 273

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

CF3SRF

+

−78
C

ClF

CF3SF2RF

+

273

½251

Cl2

RF = CF3, C2F5, n-C3F7

F2, −196
C

(CF3)2S

C2F6

½255

(CF3)2SO

(CF3)2SF2

i, ii, iii

Ar2S2

ArSF5 i, F2/N2(1:9 v/v), MeCN, −5
C

Ar =

½252
254

ii, F2, CH3CN, Micro-reactor

NO2 F

iii, AgF2, CF2ClCFCl2, 60−130
C, Cu

Ar = NO2

Figure 8.92

SF5Br

+

CF2=CFPh

hν SF5CF2CFBrPh

AgBF4

SF5CF2CF2Ph

½256

Figure 8.93

Cl

S

Cl

Cl

S

Cl

i

F

S

F

F

S

F

8.94A

ii

2 CF2=S

½233

8.94B i, SbF3/90
C ii, 457−500
C

Figure 8.94

A general route to perfluorothioketones has been developed [258] involving reaction of appropriate bis-organomercurials with sulphur vapour (contact at lower temperatures gives polysulphides) (Figure 8.95). (CF3)2CFHgCF(CF3)2 + S

445
C

(CF3)2C=S + HgF2

½258

60%

Figure 8.95

Thioketones may also be obtained by heating perfluoroalkyl iodides with phosphorus pentasulphide [258] (Figure 8.96).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 274

274

Chapter 8 i

C2F5CFICF3

½258

(C2F5)CF3C=S

i, P2S5, 550
C

Figure 8.96

Hexafluorothioacetone does not readily form a hydrate, but dimerises readily, particularly in the presence of base; high temperatures are then required to reverse the process [258] (Figure 8.97). 2(CF3)2CS

Base

F3C

S

CF3

600
C

F3C

S

CF3

½258

Figure 8.97

The dimer of hexafluorothioacetone may also be obtained from hexafluoropropene [259] and the former has now been used in a route to a sulphene [260] (Figure 8.98). CF3CF=CF2

F3C F3C

SO2

−

+

−

F

(CF3)2CF

CF3

i

S

CF3

F3C

S

CF3

−

½259, 260

(CF3)2CFS

(CF3)2C=S

CF3

S

F3C

Sx

i, Quinuclidine

(CF3)2C=SO2

Figure 8.98

Bistrifluoromethylthioketene has been obtained as a monomer; that is very unusual, since thioketenes generally dimerise [261] (Figure 8.99). EtOOC

COOEt

S

i (CF3)2C

EtOOC

COOEt

C(CF3)2

70%

½261

S 750
C/1mm

i, SF4, HF, 125−200
C (CF3)2C=C=S

70%

Figure 8.99

The nickel–dithiolene complex (Figure 8.100) is considered as a potential means of recovering ethene, because it is capable of binding ethene reversibly by a redox-switch process [262].

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 275

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives F3C

S

CF3

S

F3C

S

CF3

CF3

S

S

CH2=CH2

Ni S

F3C

275

½262

Ni S

F3C

S

CF3

Figure 8.100

III

NITROGEN DERIVATIVES

A

Amines

Primary and secondary perfluoroalkylamines are relatively unstable systems with respect to the elimination of hydrogen fluoride, although the situation is not as extreme as that obtained with the corresponding alcohols. Consequently, CF3 NH2 has been characterised when generated at low temperatures [139] (Figure 8.101). CF3NCl2 + HCl

Base

CF3NH2.HCl

½139

CF3NH2

Figure 8.101

Ammonia reacts readily with fluoroalkenes (see Chapter 7) but amines are not isolated from these reactions [230] (Figure 8.102) CF2=CF2

+

−2HF

HCF2CF2NH2

NH3

½230

HCF2CN

R

R

N N

N

R = CF2H R

Figure 8.102

Addition of hydrogen fluoride [263, 264] to the imine CF3 N5CF2 occurs and this secondary system is reasonably stable, allowing some further reactions to be carried out [263–265] (Figure 8.103). Other perfluorinated secondary amines have also been isolated [266–268]. CF3N=CF2 + HF

(CF3)2NH

i

(CF3)2NH

(CF3)2N NO2

i, HNO3, (CF3CO)2O

Figure 8.103

½263, 264 ½264

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276

Chapter 8

Systems in which the nitrogen is attached to carbon bearing only perfluoroalkyl groups, rather than fluorine, are particularly stable but weak bases; for example, perfluorot-butylamine is practically devoid of basic properties [269] (Figure 8.104). Diazotisation of the amine gives a mixture of the alcohol and the nitroso derivative [270] (Figure 8.105). i

ii

(CF3)3CNHOH

(CF3)3CNO

(CF3)3CNH2

½269

i, H2/Pd black; ii, HI, Red P

Figure 8.104

i

(CF3)3COH

(CF3)3CNH2

+

(CF3)3CNO

½270

i, HNO2, 0
C

Figure 8.105

Fluoroalkylbenzylamines are obtained by the Lewis-acid-catalysed reactions of fluoroalkylimines with aromatic compounds [270], and reactions also occur with alkenes [270, 271] (Figure 8.106). (CF3)2C=NH

+

i

CH3OC6H5

C(CF3)2NH2

CH3O

½270

i, AlCl3, 150
C (CF3)2C=NH

+

i

CH2=CHCH3

CH2=CHCH2C(CF3)2NH2

½270

i, AlCl3, 100
C H (CF3)2C=NH

+

CH2=CHCH=CH2

i, ii

N

CF3

½271

CF3

i, 100
C, 13hr; ii, 150
C, 6hr

Figure 8.106

The fluoroalkylbenzylamines are characterised by their particular inertness [270], being devoid of the tendency towards oxidative decomposition that is generally characteristic of amines. In fact, oxidation of methyl will occur in preference to that of an amino group in these systems (Figure 8.107). H3C

i C(CF3)2NH2 i, Na2Cr2O7, H2SO4

Figure 8.107

HOOC

C(CF3)2NH2

½270

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 277

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

277

Perfluoro tertiary amines ðRF Þ3 N are very inert systems and are more akin to perfluoroalkanes than amines. They are most directly obtained by electrochemical fluorination [272, 273] (see Chapter 2, Section III) and, as inert volatile fluids, they are used commercially as evaporation coolants for electronic apparatus. Electron-diffraction studies on ðCF3 CF2 Þ3 N have suggested susceptibility to attack at the CF2 positions by electrophiles [274].

B 1

N–O compounds Nitrosoalkanes

Trifluoronitrosomethane may be obtained from photolysis of a mixture of trifluoroiodomethane and nitric oxide [275, 276] or from pyrolysis of trifluoroacetyl nitrite [277, 278] (Figure 8.108). hν, Hg CF3I

+

(CF3CO)2O

NO

+

CF3NO

N2O3

½276

80%

CF3COONO

½277, 278

92%

190
C CF3NO

+

CO2

56%

Figure 8.108

Trifluoronitrosomethane is unusual among nitroso compounds in that it exists as a monomer that is deep blue and is therefore one of the few highly coloured simple polyfluoro compounds. On photolysis, a species derived from radical coupling is formed [276] (Figure 8.109). hν CF3

CF3NO CF3

CF3NO

(CF3)2NO

½276

NO

(CF3)2NO (CF3)2NONO

CF3NO

+ CF3

Figure 8.109

A series of nitroso rubbers has been formed by reaction of trifluoronitrosomethane with fluoroalkenes [279]; with tetrafluoroethene an oxazetidine and a 1:1 copolymer are obtained (Figure 8.110), the polymer being formed in preference at lower temperatures [279–281]. It is claimed that the mechanism involves electron transfer [282]. F3C CF3NO + CF2=CF2

Figure 8.110

N

O F

CF2CF2N(CF3)O

n

½280

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 278

278

Chapter 8

2 Bistrifluoromethyl nitroxide Bistrifluoromethyl nitroxide, ðCF3 Þ2 NO, is a stable purple gas and is of particular interest because, of course, nitroxides are stable free radicals. The nitroxide is prepared from bistrifluoromethylhydroxylamine [283] by reaction with, for example, silver oxide [284] (Figure 8.111) or potassium permanganate [285]. hν

CF3NO

(CF3)2NONO

HCl, H2O

(CF3)2NOH

AgO

(CF3)2NO

½284

Quantitative

Figure 8.111

A range of products containing ðCF3 Þ2 NO groups may be obtained by addition to unsaturated compounds [286–289] (Figure 8.112). (CF3)2NO

i

CF2=CFCF3

+

(CF3)2NOCF2CF(CF3)ON(CF3)2

½287

i, 15 min., rt i (CF3)2NO

+

F

C6F6-n[ON(CF3)2]n

i, Sealed tube, 150
C, 1−4hr

½288

n = 2,4,6

Figure 8.112

C Aza-alkenes In contrast to the limited chemistry of fluorinated amines, a large number of aza-alkenes and -dienes have been synthesised and these have an extensive chemistry. Some routes to aza-alkenes and -dienes [96] are illustrated in Table 8.5; some were included earlier (Section IB) in the variety of heterodienes that are obtained from hexafluoroacetone. Table 8.5 Preparation of aza-alkenes and -dienes Reaction

Ref.

F 3C N O

i

F

CF3N=CF2

[280]

i, Si tube, 550
C, 5mm i

(CF3)2NCOF

CF3N=CF2

96%

[290]

i, Ni tube, 576
C

(C2H5)2NH

i

(C2F5)2NF

ii

C2F5N=CFCF3

[291] i, Electrochem. fluorination; ii, (C5H5)2Fe

Contd

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 279

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

279

Table 8.5 Contd Reaction

Ref. i

(CF3)2C=NH + CCl4

(CF3)2CClN=CCl2

i, AlCl3, 65−100
C; ii, KF, Sulpholan

82%

ii

[292]

(CF3)2C=NCF3 + (CF3)2CFN=CF2 70 : 30 92% total i

F

F N

F

N

N

i

[293]

CF3

i, Mild Steel, 400−600
C

CF3CHFCF2N3

CF3CF2CF2CF=NCF3

F

CF3CHFN=CF2

CF3CH=NCF3

[294, 295]

i, Pt, 270−280
C i

CBr2=NN=CBr2

CF3N=NCF3

92%

i, AgF2, 100
C 70
C

AgF

[296] i

CF2=NN=CFBr

CF2=NN=CF2

33% overall

i, AgF, 125
C CCl2N=CCl2

HF

CF2NHCF3

2

NaF, 50
C 2

CF=NCF3

[297] 2

N

N i

F

F

[298]

N

N i, CoF3.CaF2, 80
C

F

N

i

F

N

N

+F

F

N

N

N

i, CoF3.CaF2, 175
C

F N

N

N

[298] + F2

F

F

N

N

RF

N

F N

RF

RF F

N

N

N

i

N

i, CoF3.CaF2, 172
C

F RF

83%

N RF = CF(CF3)2

[299] Contd

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 280

280

Chapter 8

Table 8.5 Contd Reaction

Ref. [300]

i

CF3CCl=NN=CClCF3

CF3CONHNHCOCF3

i, PhNMe2.HCl, POCl3 CF2=CFCF3 +

[301]

CF3CHFCF2N3 + CF3CF=CFN3 25%

−

Distil

i, Et4N N3 , −5
C F3C

F3C

F

F

F

N <5%

F N 25%

Polyfluoroaza-alkenes are even more susceptible to nucleophilic attack than polyfluoroalkenes. Hydrolysis of CF2 5NCF3 occurs readily giving the isocyanate [302, 303], and a variety of reactions with nucleophiles have been recorded (Figure 8.113). i

CF3N=CF2

CF3NCO

½302

50%

i, H2O, 20
C, 24hr CF3N=CF2

+

CH2=CHCH2OH

i

CF3NHCO2CH2CH=CH2

52%

½304

i, aq KF, Et2O CF3N=CF2

+

CH2=CHCH2OH

Et3N

CF3N=C(OCH2CH=CH2)2

½304

Figure 8.113

Anions may be generated by reaction of fluoride ion with polyfluorinated aza-alkenes in a manner similar to that described earlier for fluoroalkenes (see Chapter 7, Section IIC, Subsection b) but, not being as readily available as fluoroalkenes, the chemistry is less well developed. Some examples of reactions induced by formation of aza-anions from aza-alkenes are shown in Figure 8.114. ½124, 305 (CF3)2NCF=NCF3 i F

CF3N=CF2

(CF3)2N ii

CF3N=CF2

(CF3)2COF

i, ii,

CF3N=CF2; CsF, COF2, 100−150
C, 2hr

+

HgF2

100
C, 15hr

[(CF3)2N]2Hg

½264

Figure 8.114 Contd

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 281

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives F3C CF3N=CF2

F

i

F3C N

N

F

ii

F

2

CF3N

281

F

F

½306

N

CF3N

F

CF=NCF3

CF3

F

−F

i, CsF, Sulpholan, −23
C ii, CF3N=CFCF=NCF3

CF3 F

CF=NCF3 94% F

N

F N

CF3

CF3N

RF

RF

RF

i

i

F

F

N

N

N

Cs

8.114B

8.114A ii

iii

½307

F

RF = (CF3)2CF

RF 8.114A F N

+ 8.114B

Ratio 4:1

i, CsF, Sulpholan; ii, CH3I; iii, BF3.Et2O

CH3

Figure 8.114 Continued.

A remarkable rearrangement occurs in the conversion of 8.115A to 8.115B and a mechanism has been advanced for the formation of a trifluoromethyl group [308] (Figure 8.115). Stable salts of the ðCF3 Þ2 N
anion have been described [309]. Oxaziridines have been obtained from perfluorinated aza-alkenes using a variety of approaches, and they have been used in oxygen transfer and other reactions [310] (Figure 8.116). Remarkably, perfluoroazapropene (8.117A) reacts with SbF5 to produce oligomers [311, 312] (Figure 8.117). Further reaction of the cyclic trimer with SbF5 leads to the loss of CF4 to give the stable cation 8.117B whereas, if the reaction is carried out in

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 282

282

Chapter 8 F F

F

F

N

N

N

N

N

½308

F N

N

F

F

N

8.115A

2 F

1

2

F

N F N N

N F N

F

N N

N

i

F

F

i,

1

CsF, 150
C, 16hr

F

F3C

F

N F

N

N CF3

F

N N

F

N

N

N F 8.115 B

F

Figure 8.115

CF3N=CF2

+

CF3OOH

O

CF3NHCF2OOCF3 N

F3C

F

½310

F

+ COF2 BrCF2CF2N=CFCF3

O

i BrCF2CF2

O

CF3

N

CF3CF2

F 55

:

CF3

N

½310

F 45

i, m-CPBA, Sulpholan, 22
C O N RF

F RF RF = n-C4F9

Figure 8.116

R1SR2

R1SOR2

+

RFN=CFRF

½310

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 283

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

F3C CF3N=CF2

CF3 N

2hr, 20
C

+ SbF5

283

N

(CF3)2NCF=NCF3

F

½311

N

8.117A

CF3 (CF3)2NCF2N=CFN(CF3)2

F3C

F

CF3 N

N

CF3 N

i

F

F

F3C N

−

8.117B

− CF4, −F

N

F

CF3

N

i, SbF5

CF3

F3C N

N

N

i

F

CFN(CF3)2

(CF3)2NCF

−2CF4

N

i, SbF5, SO2 CF3

CF3 N

N

CF2

F2C

C F2

F2C

N

CF3

CF3N=CF2 CF3

CF3 N

N C F2

N C F

CF3N=CF2

N

½312

8.117C

CF3

F2C

½312

F

F2C

CF2

N C

CF3

F CF3 N F2C

N C

CF3

F

Figure 8.117

sulphur dioxide as solvent, then the major product is the cation 8.117C. The reactions probably proceed via the aza-allyl cation, following reaction paths similar to those described for the oligomerisation of hexafluoropropene, via the perfluoroallyl cation outlined in Chapter 7, Section IID.

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 284

284

Chapter 8

D Azo compounds A synthesis of hexafluoroazomethane from tetrabromoazomethane has already been referred to [296], and some other routes to polyfluoroazoalkanes are illustrated in Figure 8.118. i CF3CN i,

C2F5N=NC2F5

90%

AgF2, Ambient Temp. i

205
C

C2F5CF2NCl2

C2F5CN

i, ClF, −78 to −0
C

CF2(CN)2

½313

ClF

C3F7N=NC3F7

½314

85%

Cl2NCF2CF2CF2NCl2

200−250
C

½314

F N

N

95%

Figure 8.118

Like the hydrocarbon analogues, highly fluorinated azo compounds break down on photolysis and pyrolysis to give nitrogen and corresponding organic radicals [315] (Figure 8.119). CF3N=NCF3 2CF3

hν

2CF3

+ N2

½315

C2F6

Figure 8.119

E

Diazo compounds and diazirines [316]

Stable diazoalkanes and diazirines (Figure 8.120, where X and Y are fluoroalkyl groups) have been isolated, but no authenticated report is available of a diazoalkane where X or Y is a fluorine atom, although difluorodiazirine is now well documented [316]. It has been suggested that this is probably yet another result of the propensity of fluorine to favour the formation of F2Cðsp3 Þ bonds, rather than F2Cðsp2 Þ, thus making the diazirine structure thermodynamically preferred, although calculations have suggested that the diazomethane structure is slightly preferred for CF2 N2 [317]. X

X C

N

N

C

Y

Y Diazoalkane

Figure 8.120

N

X

N

Y

N

N

Diazirine

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 285

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

285

Oxidation of fluorinated hydrazones with lead tetra-acetate forms a useful method for the synthesis of bis(perfluoroalkyl)diazomethanes [318] (Figure 8.121). (CF3)2CO

+

i

NH3

(CF3)2C=NH

½103

70%

i, Pyridine, −25 to −30
C (CF3)2C=NH

+

NH2NH2

i

(CF3)2C=NNH2

68%

½103

i, P2O5, 0
C i

(CF3)2C=NNH2

(CF3)2CN2

½318

77%

i, Pb(OAc)4, C6H5CN, 0
C

Figure 8.121

Diazotisation of hexafluoroisopropylamine has also been achieved [319] (Figure 8.122). CF3CF=CF2

ii

i

(CF3)2CHNH2

(CF3)2CFNO2

75%

½319

i, HF/HNO3; ii, H2, Pd, 70
C, 100atm (CF3)2CN2

(CF3)2CHNH2.HCl

½319

48%

Figure 8.122

Bis(perfluoroalkyl)diazoalkanes are surprisingly stable; for example, deliberate attempts to detonate 2-diazoperfluoropropane failed [318]. It has been emphasised [316, 319] that this compound is less readily attacked by electrophilic reagents than diazoalkanes but is unusually susceptible to nucleophilic attack, which is a consequence of electron withdrawal by trifluoromethyl (Figure 8.123). (CF3)2CN2

+

N

(CF3)2CHN=N

N

½318

Figure 8.123

Additions to some unsaturated compounds occur [318] (Figure 8.124). In the case of diazirines, both difluorodiazirine and bis(trifluoromethyl)diazirine have been obtained. Difluorodiazirine was originally prepared by reductive defluorination of bis(difluoroamino)difluoromethane [320, 321], but it can also be obtained by an interesting fluoride-ion-induced rearrangement of difluorocyanamide [322] (Figure 8.125). Bis(trifluoromethyl)diazirine [318, 323] is best obtained by the oxidation of 2,2-diaminohexafluoropropane, prepared from hexafluoroacetone, with sodium hypochlorite (Figure 8.126). Loss of nitrogen from these aziridines occurs on photolysis and pyrolysis, and a number of the subsequent reactions have been formulated as reactions of the carbenes F2 C : and CF3 Þ2 C : , which have also been discussed earlier; see Chapter 6, Section IIIA.

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286

Chapter 8

CN (CF3)2CN2 + CH2=CHCN

60
C

F3C

½318

N

F 3C

N

CN F3C

N

F3C

N H

(Quant.) CH3

H3C (CF3)2CN2 + CH3C

150
C

CCH3

F3C

½318

N

F3C

N

H3C

CH3

400
C F3C

CF3 56%

Figure 8.124

i

F

N

F

N

CF2(NF2)2

½321

i, (C5H5)2Fe, (C2H5)4NCl (or I)

i

F2NCN

H2NCN(H2O)

20%

½322

i, F2, He, Buffered, 5−9
C

CsF/24
C

F

N

F

N

F2NCN F

½322 F

N

N

F N F

Figure 8.125

F F

N F

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 287

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives i

F

N

F

N

(CF3)2C(NH2)2

287

78%

½323

i, NaOCl, NaOH, 40−60
C

Figure 8.126

REFERENCES 1 2 3 4 5 6 7 8 9 10

11 12 13 14 15 16 17 18 19 20 21 22 23

24 25 26 27 28 29

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W.R. Brasen, H.N. Cripps, C.G. Bottomley, M.W. Farlow and C.K. Krespan, J. Org. Chem., 1965, 30, 4188. G.V.D. Tiers, J. Fluorine Chem., 1998, 90, 97. R.N. Haszeldine and J.M. Kidd, J. Chem. Soc., 1953, 3219. C.W. Tullock and D.D. Coffman, J. Org. Chem., 1960, 25, 2016. J. Burdon in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorine Compounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 655. W.E. Truce, G.H. Birum and E.T. McBee, J. Am. Chem. Soc., 1952, 74, 3594. R.D. Chambers and R.H. Mobbs, Adv. Fluorine Chem., 1965, 4, 50. W.A. Sheppard, J. Org. Chem., 1964, 29, 895. S. Andreades, J.F. Harris and W.A. Sheppard, J. Org. Chem., 1964, 29, 898. A.L. Clifford, H.K. El-Shamy, H.J. Emele´us and R.N. Haszeldine, J. Chem. Soc., 1953, 2372. G.A. Silvey and G.H. Cady, J. Am. Chem. Soc., 1950, 72, 3624. E.A. Tyczkowski and L.A. Bigelow, J. Am. Chem. Soc., 1953, 75, 3523. R.M. Rosenberg and E.L. Muetterties, Inorg. Chem., 1962, 1, 756. S. Temple, J. Org. Chem., 1968, 33, 34. D.T. Sauer and J.M. Shreeve, J. Chem. Soc., Chem. Commun., 1970, 1679. R.D. Bowden, P.J. Comina, M.P. Greenhall, A. Loveday and D. Philip, Tetrahedron, 2000, 56, 3399. R.D. Chambers and R.C.H. Spink, J. Chem. Soc,. Chem. Commun., 1999, 883. A.M. Sipyagin, C.P. Bateman, Y.-T. Tan and J.S. Thrasher, J. Fluorine Chem., 2001, 112, 287. E.W. Lawless, Inorg. Chem., 1970, 9, 2796. R.W. Winter, R. Dodean, J.A. Smith, R. Anilkumar, D.J. Burton and G.L. Gard, J. Fluorine Chem., 2003, 122, 251. W. Sundermeyer and W. Meize, Z. Anorg. Allg. Chem., 1962, 317, 334. W.J. Middleton, E.G. Howard and W.H. Sharkey, J. Org. Chem., 1965, 30, 1375. D.C. England, J. Org. Chem., 1981, 46, 153. U. Hartwig, H. Pritzkow, K. Rall and W. Sundermeyer, Angew. Chem., Int. Ed. Engl., 1989, 28, 221. M.S. Raasch, J. Org. Chem., 1970, 35, 3470. K. Wang and E.I. Stiefel, Science, 291, 106. D.A. Barr and R.N. Haszeldine, J. Chem. Soc., 1955, 2532. J.A. Young, S.N. Tsoukalas and R.D. Dresdner, J. Am. Chem. Soc., 1958, 80, 3604. F.S. Fawcett, C.W. Tullock and D.D. Coffman, J. Chem. Eng. Data, 1965, 10, 398. R.E. Banks and G.J. Moore, J. Chem. Soc. (C), 1966, 2304. R.E. Banks, R.N. Haszeldine and R. Hatton, J. Chem. Soc. (C), 1967, 427. R.E. Banks, W.M. Cheng and R.N. Haszeldine, J. Chem. Soc., 1964, 2485. I.L. Knunyants, B.L. Dyatkin and E.P. Mochalina, Bull. Acad. Sci. USSR, 1965, 1056. D.M. Gale and C.G. Krespan, J. Org. Chem., 1968, 33, 1002. Y.V. Zeifman, N.P. Gambaryan and I.L. Knunyants, Bull. Acad. Sci. USSR, 1965, 1431. S. Nagasi, Fluorine Chem. Rev., 1967, 1, 77. F.G. Drakesmith in Organofluorine Chemistry. Techniques and Synthons, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 197. M. Gaensslen, U. Gross, H. Oberhammer and S. Rudiger, Angew. Chem., Int. Ed. Engl., 1992, 31, 1467. R.N. Haszeldine, J. Chem. Soc., 1953, 2075. A.H. Dinwoodie and R.N. Haszeldine, J. Chem. Soc., 1965, 1675. C.W. Taylor, T.J. Brice and R.L. Wear, J. Org. Chem., 1962, 27, 1064. R.E. Banks, M.G. Barlow, R.N. Haszeldine and M.K. McGrath, J. Chem. Soc. (C), 1966, 1350.

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M.C. Henry, C.B. Griffis and E.C. Stump, Fluorine Chem. Rev., 1967, 1, 1. D.A. Barr and R.N. Haszeldine, J. Chem. Soc., 1955, 1881. J.M. Birchall, A.J. Bloom, R.N. Haszeldine and C.J. Willis, J. Chem. Soc., 1962, 3021. V.A. Tinsburg, A.N. Medvedev, S.S. Dubov, P.O. Gitelv, V. Smolyanitskaya and G.E. Nikolaneko, J. Gen. Chem. USSR, 1969, 39, 262. R.N. Haszeldine and B.J.H. Mattinson, J. Chem. Soc., 1957, 1741. W.D. Blackley and R.R. Reinhard, J. Am. Chem. Soc., 1965, 87, 802. S.P. Makarov, A.Y. Yakubovich, S.S. Dubov and A.N. Medvedev, Zh. Vses. Khim. Obshchestva im. D.I. Mendeleeva, 1965, 10, 106; Chem. Abstr., 1965, 62, 16034. S.P. Makarov, M.A. Englin, A.F. Videiko, V.A. Tobolin and S.S. Dubov, Dokl. Akad. Nauk. SSSR, 1966, 168, 344; Chem. Abstr., 1966, 65, 8742. R.E. Banks, R.N. Haszeldine and M.J. Stevenson, J. Chem. Soc. (C), 1966, 901. M.A. Englin and A.V. Mel’nikova, Zh. Vses. Khim. Obshchest., 1968, 13, 594; Chem. Abstr., 1969, 70, 28503. R.E. Banks, R.N. Haszeldine and T. Myerscough, J. Chem. Soc. (C), 1971, 1951. J.A. Young, T.C. Simmons and F.W. Hoffman, J. Am. Chem. Soc., 1956, 78, 5637. R.A. Mitsch, J. Am. Chem. Soc., 1965, 87, 328. V.A. Petrov, J. Fluorine Chem., 2001, 109, 123. R.E. Banks, W.M. Cheng and R.N. Haszeldine, J. Chem. Soc., 1962, 3407. I.L. Knunyants, E.G. Bykhovskaya and V.N. Frosin, Dokl. Akad. Nauk. SSSR, 1960, 132, 357; Chem. Abstr., 1960, 54, 20841. R.E. Banks, D. Berry, M.J. McGlinchey and G.J. Moore, J. Chem. Soc. (C), 1970, 1017. R.A. Mitsch and P.M. Ogden, J. Org. Chem., 1966, 31, 3833. H.J. Scholl, E. Klauke and D. Lauerer, J. Fluorine Chem., 1972/73, 2, 205. R.D. Chambers, D.T. Clark, T.F. Holmes, W.K.R. Musgrave and I. Richie, J. Chem. Soc., Perkin Trans. 1, 1974, 114. R.N. Barnes, R.D. Chambers, R.D. Hercliffe and W.K.R. Musgrave, J. Chem. Soc., Perkin Trans. 1, 1981, 2059. M. Barlow, D. Bell, N.J. O’Reilly and A.E. Tipping, J. Fluorine Chem., 1983, 23, 293. C.S. Cleaver and C.G. Krespan, J. Am. Chem. Soc., 1965, 87, 3716. D.A. Barr and R.N. Haszeldine, J. Chem. Soc., 1956, 3428. J.A. Young, W.S. Durrell and R.D. Dresdner, J. Am. Chem. Soc., 1959, 81, 1587. V.G. Andreev, A.F. Kolomiets and G.A. Sokolskii, Izv. Akad. Nauk. SSSR, Ser. Khim., 1990, 1643; Chem. Abstr., 1990, 113, 1643. F.S. Fawcett, C.W. Tullock and D.D. Coffman, J. Am. Chem. Soc., 1962, 84, 4275. R.N. Barnes, R.D. Chambers, M.J. Silvester, C.D. Hewitt and E. Klauke, J. Fluorine Chem., 1984, 24, 211. R.N. Barnes, R.D. Chambers and R.S. Mathews, J. Fluorine Chem., 1982, 20, 307. R.N. Barnes, R.D. Chambers and C.D. Hewitt, J. Fluorine Chem., 1986, 34, 59. U. Heider, M. Schmidt, P. Sartori, N. Ignatyev and A. Kucheryna, Eur. Pat. 1 081 129 (2001); Chem. Abstr., 2001, 134, 207547. V.A. Petrov and G. Resnati, Chem. Rev., 1996, 96, 1809. I.L. Knunyants, A.F. Goutar and A.S. Vinogradov, Izv. Akad. Nauk. SSSR, Ser. Khim., 1983, 476; Chem. Abstr., 1983, 99, 53706k. G. Pawelke and H. Burger, J. Fluorine Chem., 1984, 26, 321. J.K. Ruff, J. Org. Chem., 1967, 32, 1675. J.B. Hynes and T.E. Austin, Inorg. Chem., 1966, 5, 488. M.E. Jacox, Chem. Phys., 1984, 83, 171. C.G. Krespan and W.J. Middleton, Fluorine Chem. Rev., 1971, 5, 57. C. Glidewell, D. Higgins and C. Thompson, J. Comput. Chem., 1987, 8, 1170. D.M. Gale, W.J. Middleton and C.G. Krespan, J. Am. Chem. Soc., 1966, 88, 3617. E.P. Mochalina and B.L. Dyatkin, Bull Acad. Sci. USSR, 1965, 899.

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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

320 321 322 323

295

R.A. Mitsch, J. Heterocycl. Chem., 1966, 3, 245. R.A. Mitsch, J. Org. Chem., 1968, 33, 1847. M.D. Meyers and S. Frank, Inorg. Chem., 1966, 5, 1455. R.B. Minasyan, E.M. Rokhlin, N.P. Gambaryan, Y.V. Zeifman and I.L. Knunyants, Bull. Acad. Sci. USSR, 1965, 746.

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Chapter 9

Polyfluoroaromatic Compounds

This chapter will deal mainly with the chemistry of highly fluorinated compounds, although this will be prefaced by a more general summary of synthetic methods for the introduction of fluorine into an aromatic system. A review of this topic by Brooke [1] covers the area in considerable detail and we can only be selective in our discussion here.

I SYNTHESIS [1, 2] A General considerations An ideal process would, in principle, be one where elemental fluorine could be used as indicated in Figure 9.1. Recent work with elemental fluorine has demonstrated that this is a reasonable approach in some circumstances, e.g. when the opportunity for forming isomers is limited. However, nucleophilic displacement of other halogens, or mobile groups such as nitro, by fluoride ion, when the aromatic compound is susceptible to nucleophilic attack, is a more versatile approach at the present time (Figure 9.2). 2ArH + F2

2HF

Electrolysis

2ArF + HF

F2 + H2

Figure 9.1

Ar

L + F

Ar

F

+

L

Figure 9.2

We are mainly concerned here with general processes but two specific reactions are of some interest. Fragmentation occurs in the pyrolysis of CFBr3 , giving perfluorobenzene (Figure 9.3) [3–5]; this was probably the first synthesis of this compound, although it was not reported for some time. Trimerisation of hexafluoro-2-butyne leads to hexakis(trifluoromethyl)benzene [6, 7], a reaction that was referred to in Chapter 7, Section IIIB, Subsection 1. 6 CFBr3

3 CF3C

Pt 630−640⬚ C CCF3

9 Br2

C6(CF3)6

Figure 9.3

296

+

Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

C6F6

55%

½4
½6, 7


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Polyfluoroaromatic Compounds

B

297

Saturation/re-aromatisation

Examples of saturation and then re-aromatisation by dehydrohalogenation and dehalogenation are given in Figure 9.4. Use of cobalt trifluoride [8] to form perfluorinated i

C6Cl6

ii

C6ClxF12-x

C6F6 C6F5Cl C6F4Cl2 C6F3Cl3

x = mainly 5, 6, and 7 i, F2, CF2ClCFCl2 ii, Fe, 330
C

C6H6

C6H3F9 etc

KOH C6F6

C6H3F7

CH3

½17


C6F5H

CF3

CF3 CoF3

½16


Fe

F

½18


F

460
C CF3

CF3

CH3

H

H i

F

−

F

2F

½13


H

H i,

Hg Cathode

F CoF3

F Fe

F

½19


F

410
C F

i N

N F i, ii,

Figure 9.4

F

Electrochemical Fluorination Fe/600
C/,1mm

F

ii

F N

½15
25%

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298

Chapter 9

saturated systems as inert liquids is an industrial process operated by F2 Chemicals Ltd.; a variety of benzenoid derivatives have been fluorinated in this way. Re-aromatisation may be achieved by essentially two procedures: either elimination of hydrogen fluoride [9, 10] using base, or defluorination over heated iron or nickel [11, 12]. The latter is a very effective process for defluorination and is frequently overlooked in more recent literature on processes for ‘activating’ carbon–fluorine bonds. An electrochemical process has also been used to defluorinate fluorocyclohexadienes [13]. Several condensed ring benzenoids have been prepared by the fluorination/defluorination procedure [1] but less success has been achieved using heterocyclic systems, although pentafluoropyridine has been made in a low-yield sequence [14, 15]. Re-aromatisation by elimination of hydrogen fluoride has been used as a route to thiophene and furan derivatives [20, 21] (Figure 9.5). H

H KOH

F S

½20


F S

KOH F O

H

H

H

H

H

H KOH

F O

F H

½21


F O

½21


O

Figure 9.5

C Substitution processes [22] 1 Replacement of H by F Reactions that lead to replacement of hydrogen by fluorine could, in principle, proceed by any of the processes outlined in Figure 9.6, and it is frequently difficult to make any meaningful distinction between the possibilities. Various electrophilic fluorinating reagents, including fluorine itself, are capable of transferring ‘Fþ ’ to an appropriate nucleophilic centre to give a s-complex 9.6A, but these electrophilic fluorinating agents are also strong oxidising agents. Consequently, the sequence could begin with a single-electron transfer [23], giving a radical cation 9.6B which, in turn, could receive a fluorine atom from the reagent, thus reaching 9.6A by two steps. Alternatively, the radical cation 9.6B could receive fluoride ion and then give a radical s-complex 9.6C. All of these processes are feasible and probably arise in different circumstances [24], albeit difficult to establish. Some examples of what might be reasonably regarded as electrophilic fluorinations are given in Figure 9.7. In the examples

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Polyfluoroaromatic Compounds

299

indicated, and others, the orientation of substitution is quite consistent with an electrophilic aromatic substitution process. F H

F "F"

H

9.6A F

H H

F F

9.6C

9.6B

Figure 9.6

½25


COOH

COOH

Solvent

F2 Solvent

98% H2SO4 CH3CN CF2ClCFCl2

F

F

F

NO2

NO2

Yield, % 84 53 0

½26


NO2

i F X

i, F2, HCOOH, 10⬚ C X = OH X = F

NO2

F

F

X

X

70% 53%

8% Trace

NO2

NO2

½26


i F Me i, F2, H2SO4, 10⬚ C

F

F

Me

Me

81%

2%

Figure 9.7

Substitution in pyridine is more consistent with an addition–elimination process (Figure 9.8).

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300

Chapter 9

½27


−HF

i H N

N i, F2, CFCl3, −78
C

N

F

F

F

−HI

i

70%

F Cl

N

Cl i, IF5/2I2

N

Cl

H

N

½28


F

I a

b 14% Cl b

N I

N

F

a

F

Figure 9.8

The occurrence of radical intermediates is evident from the product of the fluorination of benzene [29] and of tetrafluoropyrimidine [30] (Figure 9.9). Xenon difluoride is reactive towards aromatic compounds [31], and selective fluorodesilylation using this reagent has also been reported [32] (Figure 9.10).

2 Replacement of 2N2þ by F: the Balz–Schiemann reaction [33, 34] In this classical reaction the leaving group, molecular nitrogen, is lost on pyrolysis and the mechanism appears to involve formation of an aryl cation which then abstracts fluoride ion [35] (Figure 9.11). This reaction has been carried out on an industrial scale in spite of the fact that the decomposition stage is potentially hazardous. Consequently, techniques have been developed that avoid isolating a solid diazonium salt [2] (Figure 9.12).

3 Replacement of 2OH or 2SH by F Another alternative to the Balz–Schiemann reaction is now available through the thermal decomposition of aryl fluoroformates or aryl thiofluoroformates [36–38], as indicated in Figure 9.13. Fluoroformates are obtained in high yields but the pyrolysis step is quite variable.

4 Replacement of Cl by F [39] The most practicable and versatile laboratory and industrial route to polyfluoroaromatic compounds involves the use of potassium fluoride in nucleophilic displacement of

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Polyfluoroaromatic Compounds

F

F

F

n = 0, 20% n = 1, 40%

F n

F

F

5%

i

N

N

F

F

8%

7%

301

½29


½30


N

F

F

F

N

N

N

i, CoF3, CaF2, 183⬚ C Coupling etc

N

N

+F

F

F

N

N

Figure 9.9

CF3C6H5

XeF2

SiMe3

meta-CF3C6H4F

SiMe3

FXe

para-CF3C6H4F

71%

XeF

F

R

R

XeF2

R

R

Figure 9.10 HNO3 ArH

ArN2 BF4

Figure 9.11

ArNO2

∆ −N2

ArNH2

Ar

BF4

ArF

+

BF3

3%

½31


½32


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302

Chapter 9

N2

NH2 COOH

F

F

COOH

COOH

i

ii

½2


OH i, NaNO2, HF/H2O ii, 58⬚ C

COOH

Figure 9.12 i COCl2

COClF i, AsF3, SbF3, or SiF4 COClF

ArXH

∆

ArXCOF

ArF

+

COX

F (X = O, S) or ArXCOCl

i

C6H5OCOF

C6H5OH i, COClF, Bu3N;

α-naphth.-OCOF

ii

C6H5F

70%

½36


99% ii, Pt Gauze, 800⬚ C ∆

680⬚ C

α -naphth.-F

25%

½37


Figure 9.13

chloride by fluoride from systems activated towards nucleophilic attack. This is often referred to as the ‘Halex’ (halogen exchange) process [2, 39] (Figure 9.14). Thermodynamic data for hexafluorobenzene with potassium and sodium fluorides (Figure 9.15) [40] illustrate the feasibility of the reaction in the case of potassium fluoride. The process was pioneered by Finger and co-workers, who appreciated at an early stage the advantages of using a dipolar aprotic solvent [41–43] (see Chapter 2, Section IIB, Subsection 1, for a fuller discussion of ionic fluorides in aprotic solvents). Examples of halogen exchange using a dipolar, aprotic solvent are shown in Figure 9.16. Hexachlorobenzene gave 1,3,5-trifluorotrichlorobenzene when DMF or DMSO2 [41] was used as solvent, although the use of N-methyl-2-pyrrolidone (NMP) [42, 43] gave some tetrafluorodichlorobenzene that could not be fluorinated further in this mixture (Figure 9.17).

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Polyfluoroaromatic Compounds

ArCl + KF

303

½2


ArF + KCl

Figure 9.14

C6Cl6(g)

+

6KF(s)

C6F6(g)

+

6KCl(s)

C6F6(g)

+

6NaCl(s)

½40


∆H298 = −126 kJmol−1

C6Cl6(g)

+

6NaF(s)

∆H298 = +63 kJmol−1

Figure 9.15

NO2

NO2 Cl

½2


F

i

71%

Cl

F i, KF, DMSO, phase transfer agent, heat

NO2

NO2

½2


i 82% Cl

Cl F

Cl i, KF, DMF, heat

Figure 9.16

Cl i

F

Cl Cl i, KF, 195⬚ C, NMP

+

C6F4Cl2 + C6F5Cl

½42, 43


Cl 23%

34%

trace

Figure 9.17

The significance of obtaining only the 1,3,5-trifluorotrichlorobenzene will become clear in later discussion of orientation of nucleophilic aromatic substitution. However, a higher temperature, permitted by the use of Sulpholan as solvent [44], gave perfluoronaphthalene from the perchloro compound (Figure 9.18).

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 304

304

Chapter 9

i Cl

F

Cl

52%

F

½44


i, KF, 235⬚ C, Sulpholan

Figure 9.18

In contrast, with Sulpholan as solvent the very reactive cyanuric chloride is converted to the fluoride, even with sodium fluoride [45]. Indeed, if the system is sufficiently activated, then hydrogen fluoride may be used for the conversion [46], and the halogen exchange step probably occurs on the protonated system (Figure 9.19). N

N i

N

Cl

N

F

N

½45


74% N

i, NaF, 245⬚ C, Sulpholan Cl N

N

HF

Cl N

N

N

N

Cl

N Cl

N

F

N

Cl

H

½46


F

H −HCl

Cl N

N

HF etc

N

N F

Cl

N

F

N

Figure 9.19

Nevertheless, reaction of perchloropyridine with potassium fluoride in Sulpholan leads mainly to 2,4,6-trifluorodichloropyridine [47] (Figure 9.20). The feature limiting the extent of fluorination is, essentially, the thermal stability of the solvent. This has been circumvented by two techniques: (a) using a melt of potassium fluoride–potassium chloride at temperatures in the region of 7508C [40]; and, more successfully, (b) employing autoclaves at high temperatures for reactions in the absence of a solvent, a technique used first to fluorinate perchlorobenzene [48, 49] and perchloropyridine [47, 50, 51] (Figure 9.21). Cl

Cl

Cl

i Cl

F

F

N

N

N

i, KF, 200⬚ C, Sulpholan

Figure 9.20

10

:

1

½47


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Polyfluoroaromatic Compounds

i

C6F3Cl3

C6F6 11% + C6F5Cl 34% + C6F4Cl2 28%

305

½40


i, KF/KCl Melt, 780⬚ C + C6F3Cl3 18% + C6F2Cl4

i

C6Cl6

0.4%

C6F6 21% + C6F5Cl 20% + C6F4Cl2 14%

½48


i, KF, Autoclave, 450−500⬚ C + C6F3Cl3 12%

Cl

i Cl

F

F

N

N

N

68%

7%

i, KF, Autoclave, 480⬚ C

½47


Figure 9.21

A general process has now evolved for the synthesis of highly fluorinated azabenzenoid compounds, involving (a) synthesis of the perchloro compound by further chlorination of partly chlorinated compounds with phosphorus pentachloride, and (b) subsequent reaction of the perchloro compound with potassium fluoride. The method is illustrated for perfluoroquinoline [52] (Figure 9.22), but the technique has also been applied to other systems (Figure 9.22b). Thus, a novel field of heterocyclic chemistry is available that is still relatively unexplored.

Cl4 Cl2, AlCl3 N

PCl5

Cl

Cl N 78%

Figure 9.22a

87%

140−160⬚ C

KF 480˚C

N

315⬚ C

F

F N

71%

½52


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306

Chapter 9

F

F

F

N

F

F N

N N N

N

F N

F

F

N

N

N F

N

N

F

F

F

F

F

N N

N

N

N

N F N

F

F N

N N

N N

Figure 9.22b Perfluorinated heterocyclic systems obtained by Halex procedures [53]

II PROPERTIES AND REACTIONS A General Perfluorobenzene and perfluorobenzenoid compounds have boiling points that parallel those of the corresponding hydrocarbons but, for perfluoropyridine and other perfluoroazabenzenoid compounds, the values are significantly lower than for their hydrocarbon counterparts (Table 9.1). The base strength of nitrogen in these perfluorinated systems is very considerably reduced compared with their hydrocarbon counterparts so that, in the nitrogen systems, it is clear that substitution of hydrogen for fluorine usually produces an overwhelming reduction of intermolecular forces, which more than offsets the increase in molecular weight. Table 9.1 Boiling points of perfluoroaromatic compounds in comparison with hydrocarbon counterparts Compound Benzene Toluene p-Xylene Pyridine Quinoline Isoquinoline Pyridazine (1,2-diazine) Pyrimidine (1,3-diazine)

Boiling point (8C) [54]

Boiling point of perfluorinated derivative (8C)

Ref.

80.1 110.6 138 115.5 237.1 243.2 208 123.5

80.2 102–103 117–118 83.3 205 212 117 89

[55] [11] [11] [55] [52] [52] [56] [55]

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Polyfluoroaromatic Compounds

307

The effect of fluorocarbon groups on the strengths of various acids and bases was discussed in Chapter 4, Section IIIA, where it was pointed out that pentafluorophenyl and pentachlorophenyl are similar in electron-withdrawing properties but are much less effective than trifluoromethyl [57]. Complexes are formed between hexafluorobenzene and aromatic hydrocarbons [58] or amines [59], and the 1:1 complex formed between hexafluorobenzene and mesitylene is stable enough to allow recrystallisation [58]. Much has been written about the nature of these complexes, e.g. dispensing with the idea that they may involve charge transfer; a recent study concludes that the complexes are formed principally through van der Waals forces [60]. X-ray crystal structures of complexes of hexafluorobenzene with various cyclic aromatic hydrocarbons reveal 1:1 alternating stacks [61]. Electron affinities for perfluoroaromatic compounds indicate that they are good electron acceptors [62].

B

Nucleophilic aromatic substitution

A considerable number of highly fluorinated aromatic compounds have now been prepared that undergo various nucleophilic aromatic substitution reactions. Taking perfluorobenzene as an example, we have the two basic requirements for nucleophilic substitution to occur readily: (a) electron-withdrawing substitutents to lower the energy of a transition state leading to the intermediate 9.23A (Figure 9.23); and (b) an atom that can leave with the bonding electron pair, which in this case is F . Indeed, just as hydrocarbon aromatic compounds provide the framework for studying electrophilic aromatic substitution, it is obvious that polyfluoroaromatic compounds are particularly appropriate systems for studying nucleophilic aromatic substitution. As we will see, problems of orientation arise that are just as fundamental to nucleophilic aromatic substitution as the classical orientation problems are to electrophilic aromatic substitution, and it should be particularly evident in this area how the chemistry of fluorocarbon systems helps to extend the mechanistic framework of organic chemistry. F

Nuc k2

k1 F

Nuc

Nuc

F

F

F5

k−1 9.23A

Figure 9.23

1

Benzenoid compounds [1]

Hexafluorobenzene will react with a wide range of nucleophilic reagents, leading to pentafluorophenyl compounds; some of these are given in Table 9.2, together with some similar chemistry of other benzenoid systems. From these direct substitution products, which are generally obtained in high yield, routes have been developed to other important functional derivatives (Table 9.3). Some of these are included but other important reactions, e.g. formation of organometallic compounds, will be covered in later discussion and are not illustrated in this table.

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308

Chapter 9

Table 9.2 Reactions of perfluorobenzenoid compounds with nucleophilic reagents and some simple interconversions Reaction

Ref.

Reactions starting from hexafluorobenzene i C6F5OCH3

ii

C6F5OH

72% i, NaOCH3, MeOH; i

[63]

58% ii, AlCl3, 120⬚ C

C6F5OH

[5]

i, KOH, t-BuOH 71% i

C6F5SH

i, NaSH, Pyridine;

ii

C6F5H

[64]

ii, Raney Ni, n-BuOH ii

C6F5SO2Cl

[65]

ii, Cl2, H2O2 ii

iii

C6F5SCH3

C6F5SO2Me

[65]

ii, Me-nitrosourea, KOH, Et2O; iii, H2O2, CH3COOH i

C6F5NH2

i, aq. NH3, EtOH, 167⬚ C;

ii

C6F5NO2

85%

[66, 67]

ii, CF3CO3H, CH2Cl2 ii

C6F5NH2HCl

[68]

ii, HCl, Et2O NaOCl

ii

C6F5N=NC6F5

C6F5NO2

[69]

48%

[70]

ii, HCO3H, CH2Cl2 ii

C6F5N2

iii F

C6F5Br

[68] ii, NaNO2, 80% HF;

iii, Cu2Br2, HBr

Contd

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Polyfluoroaromatic Compounds

309

Table 9.2 Contd i

ii

C6F5NHNH2

C6F5C6H5 74%

71%

[71]

i, NH2NH2.H2O, EtOH; ii, Ca(OCl)2, C6H6 H NaOH

[72]

90%

F

H NO2Cl

LiAlH4

C6F5N3

[71]

52%

[73] C6F5H OCH2CH2OH

i

O

ii F

[74]

F O

i, (CH2OH)2, NaOH;

ii, K2CO3, DMF, Reflux

Reactions of other perfluorobenzenoid compounds NHNH2 i

F

F

F

F

[75]

iii

ii

H F

F

i, NH2NH2, aq. EtOH; ii, LiAlH4, Et2O; iii, Fehlings soln. H F

i

F

F

F

[76]

H i, LiAlH4, THF i F

F

i, C6F5O , DMAC

F

F

OC6F5

[77]

90 %

Contd

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 310

310

Chapter 9

Table 9.2 Contd i F

H2NHN

F

F

F

NHNH2 18%

i, NH2NH2, aq. EtOH H2NHN

a

F

[78, 79]

F 72%

DMAC, dimethylacetamide. Table 9.3

Nucleophilic substitution in C6 F5 X compounds Orientation of product(%)

Substituent, X H Me

CF3

NH2

NO2

NH2

OH

Nucleophile LiAlH4 NaOMe/MeOH MeLi MeO NH3 LiAlH4 NH3 EtO NH3 NH3 MeNH2 NH3 (ether) NH3 (liq.) MeNH2 (benzene) MeOH ðEt2 OÞ MeOH ðEt2 OÞ NH3 NH3 MeNH2 KOH

Ortho

Meta

Para

Reference

7 3 — — — — — — — — — 70 33 77 8 50 — — — —

1 — — — — — — — 100 87 88 — — — — — 100 87 88 100

92 97 100 100 100 100 100 100 — 13 12 30 67 23 92 50 — 13 12 —

[80] [81] [82] [83] [83] [84] [84] [84] [66, 73] [85, 86] [86] [67] [87] [88] [89] [88] [66, 73] [85, 86] [86] [73, 83, 90]

Orientation and reactivity: [1, 91]: Reactions of pentafluorophenyl derivatives are particularly interesting because of the unusual orientation of substitution observed. This area was pioneered by workers at the University of Birmingham (UK) [1, 17] and, in most cases, for substitution in C6 F5 X derivatives the main (>90%) product arises from displacement of a fluorine atom that is para to the substituent group X (for example, where X ¼ H, CH3 , SCH3 , CF3 , NðCH3 Þ2 , SO2 CH3 , NO2 , C6 F5 , OC6 F5 , etc.). In a few cases ðX ¼ NH2 , O Þ meta replacement predominates, whilst (for X ¼ OCH3 and NHCH3 ) comparable amounts of meta and para replacement occur (Figure 9.24). The effects of substituents on rate constants are, however, in the direction expected for nucleophilic aromatic substitution; electron-donating groups deactivate while electronwithdrawing groups activate; for example, C6 F5 NH2 and C6 F5 O are strongly deactivated. The magnitude of these effects, such as the relative reactivities of NaOCH3 ðCH3 OH at 608C), have been recorded [92] and some relative rates towards sodium pentafluorophenoxide (dimethylacetamide, 1068C) are shown in Table 9.4 [93].

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Polyfluoroaromatic Compounds

311

X

F X

+

F e.g. X = H, CH3, CF3

Nuc Nuc

F Nuc

X +

F

F

Nuc

e.g. X = NH2, O

Figure 9.24 Table 9.4 Relative rates of reaction of C6 F5 X towards NaOC6 F5 , DMAC [93] X CF3 CO2 C2 H5 C6 F5 Br Cl H F

Relative reaction rate 2.4  104 2.9  103 7.3  102 39 32 1 0.91

Clearly, therefore, there is a very wide spread in reactivity, as in electrophilic substitution in benzene derivatives, but here we have the contrasting feature that the orientation pattern is relatively insensitive to the substituent. Consequently, it is important to establish the nature of this unusual orientating influence arising from the five fluorine atoms. Mechanism [91, 94]: It is reasonable to assume the normal two-step mechanism (Figure 9.23) of nucleophilic attack in these systems, with the first stage k1 being rate-limiting. The type of evidence that allows this assumption to be made is that perfluorobenzene is much more reactive than perchlorobenzene, and this is only consistent with there being little or no bond breaking in the rate-determining stage. The reason for this greater reactivity of C2F over C2Cl lies in the fact that the C2F bond is more polarised and hence ion–dipole interactions with the incoming nucleophile are greater for C2F and lead to a corresponding lowering of the activation energy. Of course, a similar argument is necessary to account for the often greater reactivity of acid fluorides RCOX (X ¼ F) over acid chlorides (X ¼ Cl) towards nucleophiles, although this is rarely emphasised. We are then left with the influence of the remaining ring fluorine atoms on the substitution process. In reality, halogen atoms that are at positions ortho, meta and para to the site of nucleophilic attack (Figure 9.25) have different effects; these separate activating influences have been derived from the data contained in Table 9.5 [91, 94].

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312

Chapter 9 Fδ δ

Nuc

Nuc ortho

F

meta

para

ortho F

meta

+ F

para

Figure 9.25

Table 9.5 Ratios of measured rate constants (CH3 O =CH3 OH, 588 C) [91, 94] kF =kH

Benzene derivatives compared H

F

F

F

vs

para-F / para-H

0.43

(Position of nucleophilic attack) a

(ie k/6)

H

H F

vs

F

meta- F / meta- H

106

H

H

H

F

a

57

H

F

F

ortho-F / ortho- H

vs

F

Statistically corrected.

In the benzenoid system, therefore, the activating effects of fluorine vary in the order meta-F > ortho-F  para-F, although this can also vary with the system (see Table 9.6). Clearly, the para-F is slightly deactivating but is not very different from H at the same position. Our problem then is to rationalise these data on the basis of the known effects of F on carbanion stabilities, which we have described earlier (see Chapter 4, Section VII) (Figure 9.26).

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Polyfluoroaromatic Compounds

313

Table 9.6 Comparison of kF =kH

MeO =MeOH, 588 C Benzene derivatives Pyridine derivatives NH3 /dioxane, 258C Pyridine derivatives C

C

Ortho

Meta

Para

57 79

106 30

0.43 0.33

31

23

0.26

C

F

Strongly Stabilising

Nuc

Slightly de-stabilising for a planar system

Nuc

F

δ−

F

F

Nuc

δ−

δ−

δ− F δ+

F

F

meta-F

F para-F

ortho-F

9.26A

9.26B

9.26C

Figure 9.26

Taking the Meisenheimer complex as a model for the transition state associated with step k1 (Figure 9.23), we can easily see why meta-F, which is adjacent to centres of high charge density, is strongly activating. Likewise, the slightly deactivating influence of fluorine at the para position (9.26B) is entirely consistent with the effect of fluorine directly attached to a planar carbanion centre. However, we would have expected ortho- and para-F to have similar effects, whereas this is clearly not the case. Consequently, it has been argued that the effect of ortho-F (9.26C) is predominantly a polar influence, enhancing the electrophilic character or ‘hardness’ of the carbon atom under attack. We might expect that the influence of this ortho-F effect would diminish as the reactivity or ‘hardness’ of the nucleophile is reduced, and the data contained in Table 9.6 support this case. We can see, therefore, that nucleophilic attack para to the substituent in C6 F5 X compounds (Table 9.3) stems from maximising the number of activating fluorine atoms [95] (Figure 9.27), where attack para to X involves all of the ring fluorine substituents in the positions that maximise their activating influence. X o m

X o

F

m

p m

o F o

4- activating F

Figure 9.27

3- activating F

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314

Chapter 9

These simple arguments may be extended [76] to account for the orientation of substitution in perfluoronaphthalene, where pm indicates ‘pseudo-meta’ (activating), and pp ‘pseudo-para’ (slightly deactivating) (Figure 9.28). pp

para pm

δ−

δ− δ−

F

δ−

pm

F

F

δ−

pm

ortho

meta

δ−

pp

meta

pm

δ−

F δ− pp

Nuc

δ − ortho F

δ− ortho

F Nuc

5- activating F

4- activating F

Figure 9.28

Clearly, attack at the b-position maximises the influence of fluorine substituents. These same approaches can be used to account for the orientation of substitution in other systems (Figure 9.29). F F

F F

F

F F F

F F

F

F F

Figure 9.29

Ortho attack [1] can occur, however. Although nucleophilic substitution at sites para to X in C6 F5 X compounds generally predominates, there are cases where specific binding interactions between the incoming reagent and the substituent X are sufficient to direct the reagent to the ortho position. Hydrogen bonding [96] (Figure 9.30) and co-ordination of X to organometallic reagents are particularly significant [97] (Figure 9.31).

O

O N

H NH2

F

Figure 9.30

½96


Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 315

Polyfluoroaromatic Compounds O

BrMgO C

C6F5COOH

O

BrMgO MgBr

C

MgBr F

NHPh

2PhNHMgBr

315

F

F

½97


NH Ph H O

HO C

NHPh F

Figure 9.31

2

Heterocyclic compounds

Pyridines and related nitrogen heterocyclic (azabenzenoid) compounds: Polyfluoroaromatic nitrogen heterocyclic systems are all activated, relative to the corresponding benzenoid compounds, towards nucleophilic aromatic substitution. The magnitude of this activation is illustrated by the effects of a ring nitrogen, relative to C2F at the same position, for attack by ammonia [91] (Figure 9.32).

N F

F

N

N

N 1

Figure 9.32

37.4

N

N

F

F

N

N >105

2000

Ratio of rate constants for attack by NH3 / aq. dioxane, 258 C

It is clear from these data that ring N is a major factor affecting reactivity and orientation of attack in these systems. Nevertheless, pentafluoropyridine reacts with various nucleophiles to give products arising from exclusive attack at the 4-position (Table 9.7), whereas 3H-tetrafluoropyridine gives a mixture of both 4- and 6-attack Table 9.7 Nucleophilic attack on pentafluoropyridine and related heterocyclic compounds, and some interconversion reactions Reaction

Ref.

Pentafluoropyridine

i

OCH3

OCH3

F

F

N

N

OCH3 i

[98, 99]

F OCH3

CH3O

N

OCH3

i, CH3ONa, CH3OH

Contd

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316

Chapter 9

Table 9.7 Contd N2

NH2 aq. NH3

i

F

F

F

Br CuBr

F

N i, aq. HF, NaNO2, −20 to −25
C

N

N

[98, 100, 101] Cu, 230
C

CF3COOOH NO2

N

F

F

N

F N OH

OCH3

i

ii F

F

N

N

10

1

OH

F

F

N

N

[102] OCH3

i, KOH, t-BuOH; ii, KOH, CH3I, 100⬚ C I i

[103]

F N

i, NaI, DMF, 150⬚ C π−C5H5Fe(CO)2 i

F

[104]

N i, [π−C5H5Fe(CO)2 ]

Perfluoroisoquinoline LiAlH4

F

F N

[105]

H

Contd

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 317

Polyfluoroaromatic Compounds

317

Table 9.7 Contd CH3O CH3ONa

F

F

F

N

OCH3

OCH3

CH3OH

aq. NaOH

[105]

F

N

F

F

F

F

[106]

NH

N OH

O

Perfluoroquinoline OCH3 i

F

F N

i, CH3ONa, CH3OH

F

F N

OCH3

AlCl3, 120⬚ C

AlCl3, 120⬚ C

OH i, H2SO4

F

ii, H2O

F N

F

F

[52, 105, 106]

N

OH

F N H

F

F O

F N

O

CH3

CH2N2, Et2O

F

F N

OCH3

Contd

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318

Chapter 9

Table 9.7 Contd Miscellaneous Perfluoro-3,3’-bipyridyl OCH3 i

F

88%

F

N

[107]

N

i, CNH3ONa, CH3OH

Perfluoropyridazine CH3O

CH3O

i

N

F

N

F N

also tri- and tetra-methoxy derivatives

N CH3O

[108]

i, CH3ONa, CH3OH

N

C6H5SNa

N

H+, H2O

(SC6H5)4

N

F

[108]

85%

F N

N

Polymer

N

[109]

H OH

O

NH2

NH2

Perfluoropyrimidine

aq NH3

N

N

or

F N

F H2N

[110]

N

OCH3 N

i

F H3CO

[110]

N

i, CH3OH, Na2CO3

(Figure 9.33). Since 4-attack (one ortho-F, two meta-F) and 6-attack (one ortho-F, two meta-F) have approximately the same activation by F substituents, it is clear that the ring N only discriminates by a factor of ca. 3.7 in favour of the 4-position. Therefore, it is clear that the F substituents determine the generally specific attack at the 4-position on pentafluoropyridine (Figure 9.34).

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Polyfluoroaromatic Compounds

319

NH2 NH3/Dioxane

F

H

H

H

F

F N

N

½76


N

H2N

1

3.7

Figure 9.33

F

δ− F

δ+ o

o

Nuc

F

m

Figure 9.34

o

o

m

m

N

Nuc

Nuc

F

F

m

N

F

N

The activating influence of the F-substituent is maximised

The positions of the most favourable monosubstitution in attack by nucleophiles are shown in Figure 9.35 for various systems; it is clear that directing effects by F have a major influence on the orientation of attack.

F

F

F

N

F

F

N F

F

N

N

N

N

N

N F

F

F

F

N

N

F

F

cf N

N

F

F

N

F

N

F

N

Figure 9.35

Of course, when bromine or chlorine is at the 4-position in the pyridine system, then attack at the 2-position is favoured (Figure 9.36). Br

F N

Figure 9.36

Br aq NH3

½100
F N

NH2

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320

Chapter 9

A rare case of preferential 2-attack occurs with potassium hydroxide in t-butanol. Here, this result has been attributed to the large steric requirement of the solvated nucleophile, and the fact that the 4-position is the most crowded site. Consequently, it is observed that 3,5-dichlorotrifluoropyridine gives preferential 2-attack with this reagent [102] (Figure 9.37). OH X

X

X i

F N

X

X

X

F

F

N

N

X = F,

90

10

X = Cl,

30

70

i, KOH, t-BuOH

½102
OH

Figure 9.37

In the case of 4-nitrotetrafluoropyridine, a 4-nitro group is in competition with ring nitrogen as an orientating influence [101]. As in the benzene series, however, the effect of the nitro group is very dependent on the nucleophile and is also affected by solvent. Much more attack adjacent to the nitro group occurs with ammonia (Figure 9.38) and, again, this can be attributed to hydrogen bonding. Displacement of the nitro group itself also occurs readily. NH2

NO2

NO 2

NO2 NH2

i F N i, NH3, Et2O

F

F

F

N

N

N

27%

48%

25%

½101
NH2

Figure 9.38

There are other cases [102, 107] where the subtle interplay of solvent and steric effects has a profound effect on orientation of substitution. Polysubstitution: Most groups introduced by nucleophilic substitution are subsequently electron-donating and therefore deactivating towards further attack; for example, attack on perfluoropyridine by methoxide becomes progressively more difficult but eventually leads to 2,4,6-trisubstitution [98, 99] (Table 9.7). In this case R in 9.39A and 9.39B (Figure 9.39) is electron-donating and so 9.39A is preferred. Examples will be discussed later where the substituent is electron-withdrawing, for example, R ¼ CF2 CF3 , and then 2,4,5-trisubstitution occurs, indicating that in this case 9.39B is preferred to 9.39A. The fact that the order of nucleophilic substitution is as indicated in Figure 9.40 allows the use of polyhalopyridines for synthesis of heterocyclic systems with unusual substitution patterns [111]. Moreover, when this methodology is applied in combination with palladium chemistry, the possibilities are extensive [112, 113] (Figure 9.41).

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 321

Polyfluoroaromatic Compounds

R

R F

F

F

F

F

Nuc

N

321

R

F

Nuc

F

F

N

R

9.39B

9.39A

Figure 9.39 1

F 3

N

2

Figure 9.40

Remarkably, we note that orientation of substitution in 2,4,6-tribromodifluoropyridine depends critically on the nature of the nucleophile. So-called ‘hard’ nucleophiles, e.g. OCH3 and NH3 , give exclusive attack at the ‘hard’ electrophilic centres, i.e. C2F, whereas ‘soft’ nucleophiles displace bromine. This is further evidence for the importance of ion–dipole interactions, regarding attack at C2F bonds. Reactions of perfluoro-quinoline and -isoquinoline with hard and soft nucleophiles have also revealed a sensitivity towards a change in orientation of attack with the nature of the nucleophile [114] (Figure 9.42). To account for these results, it has been suggested that the 1-position, i.e. the position adjacent to the ring N, is the harder electrophilic site [114]. In the quinoline system the nature of the substituent groups also can govern the position of entry of a nucleophile. When R in 9.43A (Figure 9.43) is electron-donating, methoxyl for example, then a 2,4,7-trisubstituted compound 9.44A is obtained (Figure 9.44), because 9.43A is preferred to 9.43B; but when R is electron-withdrawing, CFðCF3 Þ2 for example, then a 2,4,6-trisubstituted compound 9.44B is obtained [115] because perfluoroalkyl groups stabilise 9.43B relative to 9.43A. Acid-induced processes: Although perfluoroaromatic nitrogen heterocyclic compounds are only weak bases, nucleophilic substitution can be induced by protonic or Lewis acids, as outlined in Figure 9.45, and interesting contrasts in orientation can sometimes be achieved because attack ortho to nitrogen is often preferred under these conditions. It is clear from the striking tendency for the protonated systems, as shown in Figure 9.46, to give attack ortho to nitrogen that, again, polar influences are extremely important in governing the reactivity of a C2F bond, at least with hard nucleophiles. In both of the examples contained in Figure 9.46, the orientation of entry of the nucleophile is changed in comparison with reaction with the neutral system. We may conclude, here, that in systems containing structure 9.47A (Figure 9.47) the positive pole involving nitrogen has significantly enhanced the reactivity of adjacent C2F bonds. It will be clear, therefore, that this is similar to the argument advanced for the activating influence of an ortho-C2F for nucleophilic attack on an adjacent 5C2F bond (9.47B).

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322

Chapter 9 H

Br i

ii F

F N

N

Br i, HBr/AlBr3, 150⬚ C;

H

ii, Pd/C/H2(4Bar), Et3N, CH2Cl2, rt

Br X2

X1 Nuc

F N

½112


Br

N

Br

X1 = X2 = OMe

Nuc = NH3

X1 = F, X2 = NH2

Br i

F N

Br

Nuc = NaOMe

Br

Br

N

H

Br

Br

Br

½112


F

½112


F RC

Br

N

C

i, CuI/(Ph3P)3PdCl2, Et3N, RC CH

C

CR

(R = C3H7 or Ph)

Y1

Br Nuc

F

F Br

N

Br

Br

Nuc = Et2NH;

Nuc = PhSH;

½112


N

Y

2

Y1 = Et2N, Y2 = Br

3:

Y1 = Br,

2

Y1

= PhS,

Y2 = Et2N 2

Y

= Br

Figure 9.41

Hydrogen halides give products where substitution para to nitrogen occurs almost as readily as at the ortho position [117], whilst Lewis acids usually give polysubstitution [118] (Figure 9.48).

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 323

Polyfluoroaromatic Compounds

F

F

323

½114


N

Nuc

X

X F

F

F

N

F

F

N

F

X

N

X

9.42A

9.42B

9.42C

Nucleophile 100%

HS , DMF/(CH2OH)2 PhS

(X = SH)

99%

, EtOH

MeO , MeOH

93%

4-NO2C6H4O , EtOH

100%

1%

7%

(X = SPh)

(X = MeO) (X = 4-NO2C6H4O)

Figure 9.42 Nuc F

F Nuc

F

etc

N

F

F

N

R

etc

F R

9.43B

9.43A

Figure 9.43 OCH3

OCH3 i F

F

F N

OCH3

N

CH3O

½116


F OCH3

9.44A

i, CH3O , CH3OH

CF(CF3)2

CF(CF3)2 CH3O i F

F N

F CF(CF3)2

i, CH3O , CH3OH

Figure 9.44

F N 9.44B

CF(CF3)2

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324

Chapter 9

Acc

F N

Nuc

F N

F

F

Nuc

N

F

F

Acc.

Acc. −F

Acc. = Electron Acceptor

F N

Nuc

Acc.

Figure 9.45 OMe i

F

F

F

F

N

N

F

F

N

OMe

ii

iii F

F

F

F

N

N

OMe

H i, = MeONa/MeOH

ii, = c. H2SO4

iii, = MeOH/Slow dilution OMe

H F

N

MeOH

F

N

35%

N

N

OMe

H2SO4

O Et N

F

Et3OBF4

F

Et H2O

N

N

MeOH

N

MeO N N MeO

Figure 9.46

F N

MeO

F

N

70%

½108, 109


Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 325

Polyfluoroaromatic Compounds H

δ−

F N

C

Nuc

F δ+ C

325

F C

Nuc

9.47B

9.47A

Figure 9.47 Cl

F

½117


i

F

F

N

F N

F

F N

Cl

Cl

57%

23% i, HCl, 100⬚ C, Sulpholan

Br

Cl F

F xs BBr3

F N

F

150⬚ C Br

88%

F

xs BCl3

½118


F

140⬚ C N

N

Cl

91%

Figure 9.48

As explained above, these are potentially important processes because introduction of bromine by these simple procedures allows access to the powerful range of palladium chemistry that is now available [112] (Figure 9.49).

3

Fluoride-ion-induced reactions

Polyfluoroalkylation: Some of the chemistry of polyfluoroalkyl anions, generated by reaction of fluoroalkenes with fluoride ion, was discussed in Chapter 7, where the analogy between the role of fluoride ion in fluorocarbon chemistry and the role of the proton in hydrocarbon chemistry was emphasised. This analogy has been extended to include reactions of polyfluorinated anions, generated in the same way, with activated polyfluoro-aromatic systems in what may be regarded as the nucleophilic counterpart of Friedel–Crafts reactions [119] (Figure 9.50). Polysubstitution raises some complications for three reasons: (a) when two polyfluoroalkyl groups are already present these can, in some cases, control the position of further substitution; (b) some of the reactions are reversible; and (c) substitution at the position most activated to attack sometimes results in crowding and therefore not the most thermodynamically stable system. This can lead to a competition between kinetic and thermodynamic control of reaction products [116, 122–128].

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326

Chapter 9

N

Br i

F N

CC3H7

C

N F

½112


ii

N

Br

C

CC3H7

i, CuI, (Ph3P)3PdCl2, Et3N ii, C3H7C CH

Figure 9.49 CF2=C

F

CF3

ArF

C

cf

CF3

C

CF3CF=CF2

F

C

CF

C

C

ArH

i

F N

F N i, KF, Sulpholan

F

Ar

H

RF

RF

F

F

N

N

i, KF, Sulpholan

CF2=CF2

Ar

½120
RF

RF = CF(CF3)2

i

RF

RF

F

F

N

N

½121
RF

RF = CF2CF3

Figure 9.50

The rather complicated system that results in the pyridine system, after the trisubstitution stage has been reached using perfluoroisopropyl anions [116, 122–124, 128], is shown in Figure 9.51. At lower temperatures, after disubstitution, further attack on 9.51D is kinetically preferred at the 5-position through 9.51B, with the perfluoroalkyl groups now controlling the orientation, as explained earlier. However, at higher temperatures, the process becomes reversible with attack by fluoride ion occurring at the 5-position in 9.51A, leading to displacement of a perfluoroisopropyl group that can then re-enter, at higher temperatures, at the 6-position via 9.51F. Attack by fluoride ion can also occur at the 4-position in 9.51A, giving the 2,5-derivative 9.51C. Finally, the situation is further

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Polyfluoroaromatic Compounds

327

complicated by the fact that the perfluoroisopropyl anion is in equilibrium with the perfluoroalkene and this produces oligomers (see Chapter 7). The crowding that arises from a perfluoroisopropyl group is reflected by the 19 F NMR spectra where, for example, for the compound 9.51D at 408 C two geometric isomers 9.51D1 and 9.51D2 may be detected [125, 126, 129], with the 4-substituent being essentially in two conformations. RF RF F N

½116, 122, 123


RF = CF(CF3)2

RF

9.51A −

−

F F

F

RF

RF

RF

F N

F

RF

F N

RF

RF 9.51B

RF RF CF(CF3)2

F N

RF

N

9.51C

RF F

−

−F

F N

RF

9.51D

RF

RF

CF(CF3)2

F

F RF

RF

9.51E

F N

RF

9.51F

−

CF3CF=CF2

−F

(CF3)2CF CF3CF=CF2 Dimers and Trimers

Figure 9.51 Contd

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 328

328

Chapter 9

CF3

F C

F

F3C F3C

CF3

F

F

N F3C

F CF3

N

F

F3C

CF3

9.51D2

9.51D1

Figure 9.51

½125, 126, 129


C

Continued.

The 2-substituent is aligned preferentially with the CF3 groups towards nitrogen and it is understandable, therefore, that the trisubstituted isomer 9.51E is more stable than 9.51A. Tetrafluoroethene leads only to the 2,4,5-trisubstituted compound [124], which does not rearrange, whilst perfluoroisobutene gives only the 2,4,6-trisubstituted compound; the 2,4,5-isomer, in this case, is probably very crowded. This variation in the orientation of trisubstitution products obtained with the alkene used is related to the reversibility of the process and to the crowding occurring in the 2,4,5-isomer. Carbanion stabilities decrease in the series ðCF3 Þ3 C > ðCF3 Þ2 CF > CF3 CF 2 and therefore reversibility and crowding also follow this series (Figure 9.52). RF RF

½121, 124


i CF2=CF2

F

F

N

N

N (RF)n

RF

i, CsF, Tetraglyme, 80
C

RF = CF2CF3 RF

CF2=C(CF3)2

F N i, CsF, Tetraglyme

i

½124


F RF

N

RF

RF = C(CF3)3

Figure 9.52

Fluoride-ion-induced rearrangements of perfluoro(alkyl-aromatic) compounds may be regarded as a further stage in the analogy between fluoride-ion- and proton-induced reactions [124, 127]. Those that have been established so far occur by intermolecular processes, as indicated by, for example, crossover experiments [116, 122, 123], whereas proton-induced rearrangements of alkylbenzenes may be intermolecular or intramolecular, depending on the system. However, intramolecular anionic migrations of polyfluoroalkyl groups remain to be found but are very unlikely. Only in the case of triazines have perfluoroalkyl groups been introduced directly from the perchloro compounds [130]. The 1,2,3triazine system gave an unusual product,

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Polyfluoroaromatic Compounds

329

arising from nucleophilic attack at N in 9.53B, accompanied by loss of fluorine from a tertiary site (Figure 9.53). A similar process occurs in the reaction of 2,3-dimethylbutadiene with 9.53B, giving the unusual spiro system 9.53D [131] (Figure 9.53), but without the loss of fluorine. F3C RF

N

Cl

CF3

RF

F RF

C

RF

RF

½130


RF

RF

RF N

N

N

N

N

N

N

N

N

N N RF

RF = C(CF3)3 9.53A

9.53B

RF RF

RF RF

RF

9.53C

RF

RF

RF

RF i N

N

N

N

N

N

½131


N N

N H3C

CH3

9.53B

H3C

CH3 9.53D

i, CH2=CH(CH3)CH(CH3)=CH2

Figure 9.53

Recent methodology, using amines as initiators to provide the active fluoride ion, in the absence of a solvent, has made access to these sytems on a large scale quite feasible [115]. A recent exciting development [132, 133] of this chemistry involves conversion of perfluoro(4,5-di-isopropyl)phthalonitrile to corresponding metal perfluorophthalocyanine complexes; for example, when perfluoro(4,5-di-isopropyl)phthalonitrile was melted with zinc acetate at 1808C, a blue-green solid was obtained which was established as the phthalocyanine derivative. These perfluoroalkyl derivatives are much more soluble than other halogenated phthalocyanines and, moreover, they appear to be excellent sensitisers for the production of singlet oxygen. Reactions involving chlorotrifluoroethene and bromotrifluoroethene introduce further complexities which are summarised in Figure 9.54 [134]. Direct substitution may occur giving 9.54A, but this is frequently accompanied by loss of Cl or Br from the side chain to give a pentafluoroethyl derivative 9.54B. Exchange is also possible (when X ¼ Br) to give 9.54C, together with a vinyl anion that may then react to give 9.54F, which is also able to form an anion 9.54E, and this anion can finally give a diaryl derivative 9.54D. Results relating to this scheme are shown in Table 9.8.

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330

Chapter 9 F

CF2=CFX

CF3CFX

½134


X = Cl, Br

F

ArFCF2CF3 9.54B

9.54A

ArFF

CF3CFX

F

ArFCFXCF3

+

CF2=CFX CF3CFX2

+

CF2CF

9.54C

ArFF F

(ArF)2CFCF3

ArFCF=CF2

ArFCFCF3 9.54E

9.54D

9.54F

Figure 9.54

Table 9.8 Polyfluoroalkylations and related reactions Reaction

Ref. N

N F N

C3F6

N

CsF N

200−300
C

N

[135]

[CF(CF3)2]nF3−n

n = 1, 39%; n = 2, 51%; n = 3, 5% RF

RF

RF RF

N

i

F N

N

F

5 C3F6 RF

N 6%

+

F

RF

N

N

N

[136]

+ RF RF

N

RF

3%

81% RF = CF(CF3)2

i, CsF, Sulpholan, 70⬚ C

RF

F

CF3CF=CFCF3

i

F N

N

[137] RF

i, CsF, Sulpholan, 100⬚ C RF = CF(CF3)CF2CF3

Contd

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Polyfluoroaromatic Compounds

331

Table 9.8 Contd CF3CF2 F

N

CF2=CFCl

CF3CF2 N

i

F

F

N

N

CF2=CFBr

F

i N

F

19%

+

CFCF3

N

[134]

N

CF3CF2

57%

i, CsF, Sulpholan, 90
C

N

CF3CFBr2

[134]

2

i, CsF, Sulpholan, 90⬚ C CF3CF2 F

N N

CF2=CFBr

CF3CF2

i

N

F

F

N

N

[134]

N CF3CF2

i, CsF, Sulpholan, 90
C F

CF3

C F3C

F

CF3C CCF3

CF3

C

C F3C

C

F n

[138]

i

N

F

F

N

N

i, CsF, Sulpholan, 110⬚ C

n = 2 and 3 F CO2Et

EtCO2C F

[138, 139]

i

EtO2CC CCO2Et

F

N

N i, CsF, Sulpholan CF3 C F3C

F

CF3C CCF3

i

C

F

CN

CN i, CsF, DMF, 125⬚ C

F n

[140]

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332

Chapter 9

The mechanism of displacement of chlorine and bromine by fluoride from the side chain of these systems is of interest. It has been suggested that an SN 20 type of displacement of fluorine from 3-trifluoromethylquinoline occurs in reactions with sodium ethoxide [141] (Figure 9.55), and a similar process could account for the displacements of chloride or bromide by fluoride from 9.54A that were indicated in Figure 9.54. EtO

CF3

H CF2

i N

OEt

½141


N i, NaOEt/EtOH/Reflux

CF=OEt

CF2OEt −F N

N

EtO

etc

CO2Et

C(OEt)3 H2O N

N

Figure 9.55

A striking example of an intramolecular nucleophilic displacement of tertiary F is shown in Figure 9.56 [142]. Further examples of polyfluoroalkylation are given in Table 9.8. Other systems: Additions of perfluoro-2-butyne [143] and acetylene dicarboxylic ester [139] to perfluoro-aromatics will also occur (see Table 9.9 and Chapter 7, Section IIIB). The extending anion may be trapped, and the more reactive the aromatic compound used, the more effective the competition with polymer formation (Figure 9.57) [144]. Cyanuric chloride, rather than the fluoride, is used for the formation of polyfluoroalkoxy derivatives [145]: the probable advantage of using the perchloro compound lies in reducing the possibility of a back-reaction when X ¼ Cl in the sequence shown in Figure 9.58.

4 Cyclisation reactions Many procedures are now available for forming cyclic systems [147] and several will be dealt with later; this section is concerned with procedures that, at some stage, involve nucleophilic aromatic substitution. In the examples shown in Figure 9.59 the addition and cyclisation occur in a single process, whereas, in other cases (Figure 9.60), an intermedi-

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Polyfluoroaromatic Compounds

333

ate is isolated before cyclisation. Polycyclic systems may be obtained from ortho-difunctional compounds (Figure 9.61). CF3

NMe2 RF

RF N F

i

N

ii

N

N

N

N

Me2N

Me2N

RF (Yellow)

RF RF = CF(CF3)2

F

RF

CF3

NMe2

iii

H3C CH3 CF3 N F3C

NMe2

C

F3C

C

F3C

C

N

N BF4

N

H2C

N N

Me2N

H3C

RF

RF

iv

(Purple)

CF3

F3C i, ii, iii, iv,

NM e

H

Me2NH/DMF/Room Temp. Standing or on addition of water BF3.Et2O Moist Acetone

H

N N

N CH3

RF

(Colourless)

Figure 9.56

CF3C CCF3 + F ArFF

CF3CF=CCF3 CF3C CCF3 CF3CF=C(CF3)C(CF3)=CCF3

ArFF CF3C CCF3

C(CF3)=CF(CF3) Polymer

Figure 9.57

n

½142


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334

Chapter 9 RFO

+

ArX

ArORF

N N

Cl

+

X

(X + Cl or F)

N

Diglyme (CF3)2CO.KF

N

−10⬚ C

½146


N

N

[OCF(CF3)2]3

86% conversion

Figure 9.58 COOEt C

i, ii

F

F

C

SH

S

i, n-BuLi ii, EtOOCC

½148


COOEt iii, −F iv, H2SO4

CCOOEt

COOEt F

CH

Cu

CH

Quinoline

C F

S

C S

COOEt

H CH3COCHCOOEt

F

Na

C

NaH

F

COOEt

C

THF O

CH3

COOEt

COOEt

C F

C

Base

C

F

CH3

O

C HO

H C F

H CH3

C F

C O

i, NaH.1THF, 2DMF reflux

Figure 9.59

CH3

H i

C O

½149


½146, 150
CH3

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 335

Polyfluoroaromatic Compounds

H C F

H

F

C O

½148


H C

i

H

C SH CH3

HS

CH3

335

i, H2S, EtOH, O⬚ C ii, Pyridine, NaOH, Reflux

ii H C F

C S

CH3

Figure 9.60

F

F

i

+ SCl2 or S2Cl2

Li Li

F

½151


F S

i, Et2O, hexane, −78⬚ C

Figure 9.61

More recently, it has been demonstrated [152] that polyhalopyridines may be used to synthesise a series of macrocycles, making use of the fact that, if the 4-position is blocked, then the remaining 2,6-sites are available to react with difunctional derivatives (Figure 9.62). X

X

F

F

N

O

X

O i

O

N

O

F

O ii

O

O

O

N O

F

N

N

O

F X X X = CF(CF3)2, 94% X = OMe, 80%

Figure 9.62

X = CF(CF3)2, 64% X = OMe, 85%

i,

Me3SiOCH2CH2OSiMe3, CsF, Monoglyme, Reflux, 2 days

ii,

Me3SiOCH2CH2OCH2CH2OSiMe3, CsF, Monoglyme, Reflux, 2 days

½152


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336

Chapter 9

C Reactions with electrophilic reagents Displacement of Fþ from an aromatic system by electrophiles is obviously not a very favourable process; indeed, fluorine might be considered as the worst possible leaving group in a non-concerted process. Nevertheless, reactions of concentrated nitric acid with perfluoro-aromatic compounds, for example perfluoronaphthalene, give quinones, or addition products may be obtained using HNO3 in HF or NO2 BF4 in Sulpholan [153]. Thus, perfluorinated systems will undergo reactions with some strong electrophiles to give products that formally arise from electrophilic displacement of fluorine, whatever the detailed mechanism may be (Figure 9.63). CH3 CH3 i F

F

½1, 154


F

F

F

F

i, CH3F, SbF5, SO2ClF, 20⬚ C

Figure 9.63

Ring fission to the phthalic acid derivative has been observed [155] (Figure 9.64). NO2 F

F i F

F

F F

F

NO2

F

½153, 155


F F

F F

F

F

61% c. HNO3

H2O

F

O

O

COOH

F

F

F

F

COOH 71%

O

F

O

F

+ i, NO2 (NO2BF4 or HNO3.HF)

Figure 9.64

Sigma-complexes have been generated, and their NMR spectra observed, by reaction of various dienes with antimony pentafluoride [156, 157] (Figure 9.65). Under certain conditions, radical cations have been observed [158] using ESR, and stable radical-cation salts have been fully characterised [159, 160] (Figure 9.66). Fluorine in the side chain can, of course, be hydrolysed under acidic conditions [18], whilst the polyfluorobenzyl cation may be obtained by removal of fluorine from perfluorotoluene [161] (Figure 9.67).

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 337

Polyfluoroaromatic Compounds O

F SF4

F

½156, 157


F

SbF5

F

337

F5 SbF6

O

H2O O

O

F

F

O

Figure 9.65

F

C6F6

+

½158


SO3.SbF5

F

F

Oleum

O2AsF6

SO3.SbF5

F

C6F6 AsF6

+

O2

½159, 160


NO

C6F6

+ NO AsF6

Figure 9.66 COOH

CF3 i

½18


F

F CF3

COOH i, H2SO4, SO3, 150⬚ C, 12hr

CF3 F

CF2 i

½161


F

i, SbF5, HF, 50-60⬚ C

CF3CF=CF2

CF2CF(CF3)2 F

Figure 9.67

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338

Chapter 9

Hydrogen in a highly fluorinated system can often be displaced surprisingly readily using electrophilic reagents (Figure 9.68); this reflects the fact that a transition state resembling that in Figure 9.69 is stabilised by fluorine atoms at the ortho and para sites by donation of electron density from the non-bonding p-orbitals on fluorine. Indeed, a perfluorinated arenium salt has been generated from perfluorocyclohexa-1,4-diene (Figure 9.65). Electrophilic cleavage of pentachlorophenylpentafluorophenylmercury provides a useful direct competition between pentafluorophenyl and pentachlorophenyl, for electrophilic attack. Exclusive attack at pentafluorophenyl occurs, showing that the cumulative activating effect of the ortho- and the para-fluorine substituents is dominant [168] (Figure 9.70).

D Free-radical attack [169] Photochemical chlorination of perfluorobenzene [170] and perfluoropyridine [171], and reactions with bistrifluoromethyl nitroxide [171], give addition products, although the C5N bond is very resistant to radical attack (Figure 9.71). It is well known that free-radical aromatic substitution occurs readily when aryl radicals are used, and extensive studies have been made using diaryl peroxides as the source of these radicals. The effect of fluorine on the process may be considered in two parts: first, most substituents may be expected to encourage the formation of radical intermediate 9.72A in Figure 9.72; second, in reactions with hydrocarbon radicals, polar effects should also increase reactivity, since the ring would be made more electrophilic. The converse would be expected to apply with electrophilic radicals, e.g. CF3  or C6 F5 . By contrast, it is not easy to predict the fate of radical 9.72A, once formed; fluorine atoms are unlikely to be generated, but transfer of a fluorine atom to another species is possible. Arylation of perfluorobenzene does indeed occur when dibenzoyl peroxide is used, but ðC6 F5 COOÞ2 gives only tar: the scheme shown in Figure 9.73 has been proposed [172–174]. In contrast, perfluoronaphthalene gives a mixture of products with benzoyl peroxide, but they mainly arise from attack by C6 H5 CðOÞO [173]. Cyclisation may be achieved in some electrochemical oxidations. These have been formulated as radical substitutions [176, 177] (Figure 9.74). Electrochemical reduction of polyhalopyridines has been observed; the position of H-transfer corresponds with calculated spin and charge densities [179] (Figure 9.75). Reductive defluorination will also occur under relatively mild conditions, in some circumstances by electron transfer from metals, e.g. zinc [180, 181] (Figure 9.76).

1 Carbene and nitrene additions Additions of carbenes to perfluorobenzene have been reported [182, 183] and tropylidene structures for the products have been proposed (Figure 9.77). Addition of difluorocarbene to perfluorobenzene has been proposed to account for the formation of perfluorotoluene and other perfluoromethylbenzenes in the pyrolysis of perfluorobenzene with potassium fluoride, or with polytetrafluoroethene as a difluorocarbene source [184, 185]. Indeed, Russian workers have studied the pyrolysis and

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Polyfluoroaromatic Compounds

339

H i

F

F

½162


CH 3

i, CHCl3, AlCl3, 150⬚ C H

Br i

F

½163


F i, Br2 (or I2), Oleum, 60−65⬚ C

H

NO2 i

F

½164, 165


F i, HNO3, Sulpholan, BF3, 60−70⬚ C CH(CH3)2

H i

F

½166


F 90-94%

i, C3H6, CBr4, AlBr3, 0⬚ C C6F5

H

3

F

SbF5,

F

½1, 154


F C6F5

C6F5

Br i

½167


F

F

i, FeBr2.CCl4, Reflux NO2 i F

F

i, HNO3, Oleum, 70⬚ C

Figure 9.68

½167


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340

Chapter 9 H

E

F5

Figure 9.69 C6Cl5Hg

H Cl

i C6F5HgC6Cl5

− C6Cl5HgCl

+

+

C6F5H

½168


F5

i, HCl, 100⬚ C, 65hr, Sealed tube

Figure 9.70 F

Cl

F

48hr

F Cl F Cl

Cl2, hn F

Cl

F Cl F Cl

Cl2, hn

35hr

N

½170


F Cl F F

Cl

Cl

F Cl F N

½171


F

Figure 9.71 R

R

F

R

F

F

F

?

F5 9.72A

Figure 9.72

co-pyrolysis of systems containing perfluoro-aromatic compounds and developed an extensive chemistry where a variety of substituents appear to be eliminated, frequently in preference to fluorine [186–188] (Figure 9.78). Elimination of difluorocarbene from a s-complex 9.79A has been proposed, although the fate of the rest of the molecule is not clear, and the addition could involve either an insertion reaction (a) or formation of a tropylidene (b) (Figure 9.79). Similar processes can be proposed to account for the formation of trifluoromethyl derivatives in the pyrolysis of heterocyclic compounds [189–193] (Figure 9.80). In contrast, a stable carbene has been synthesised having a push–pull combination of electron donation and withdrawal [194] (Figure 9.81).

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Polyfluoroaromatic Compounds

F

Ar

F

Ar

ArCOO

Ar

341

F5

ArCOOF

F

½172, 174, 175


Coupling

F

Ar F

F

F

Ar

Figure 9.73

−e

C6F5NH2

C6F5NH2

−H

½177


C6F5NH C6F5NH2 H N

N

−e

F

F

F

etc

N

F H2N

O

O

C

C

F

F

F H2N

F

F

½178


N H

Figure 9.74

Insertion of nitrenes occurs readily and may lead to ring expansion and a variety of rearrangements [195, 196] (Figure 9.82). Cyanotetrafluorophenylnitrene gives very high yields of C2H insertion compounds [197] (Figure 9.83).

E 1

Reactive intermediates Organometallics

Fluorocarbon organometallic compounds [198, 199] are discussed more generally in Chapter 10, but polyfluoroaryl-lithium, -magnesium and -copper compounds are particularly important in organic synthesis, as outlined below.

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342

Chapter 9 X

X

X

½179


i

F N

N

F4

N

ii

H

H

X

F4

F N X = Cl, F

N

F4

i, Hg Cathode, DMF, Et4NBF4, −1.8V (SCE) ii, Hydroquinone

Figure 9.75 CF3

CF2(CH2)5CH3

CH3

CF3

½180
H

i F

F

F

F

CF3

CF3

CF3

CF3

i, Zn (Cu), DMF, H2O, 1-Hexene, 65⬚ C COOH

COOH

½181


i F

F

F

F

H i, Zn, aq.NH3, rt, 2hr

Figure 9.76

C6F6 +

C6F6

hν N2

+ (CF3)2CN2

30%

F

CF3

hν

20%

F

½182


½183


CF3

Figure 9.77

Lithium and magnesium derivatives: Bromopentafluorobenzene forms a Grignard reagent readily [163] which can be used in conventional ways in syntheses [200, 201] (Figure 9.84). The tetrafluoropyridyl compound can be obtained in a similar way [98, 100, 103].

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 343

Polyfluoroaromatic Compounds C6F6 +

550⬚ C

CF2CF2

C6F6

n

343

½185


+ C6F6-n(CF3)n n = 1,2,3

CF2 C6F5X

C6F5CF2

CF2=CF2

½186


C6F5CF2CF2CF2 −F (?)

F

F

Figure 9.78

F

F

F

C6F6

CF2

(KF)

F5 9.79A

(b) Addition

(a) Insertion

C6F6

C6F6 F C6F5CF3

F

F

F F F

F F

Figure 9.79

CF3 F3C F

550⬚ C CF2CF2

n

N

CF3

F

F

N

N

60%

6%

CF3 F

i

N i, KF, 8hr, 550−560⬚ C

Figure 9.80

F N

85−90% +2- and 4- isomers

½193


½189


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344

Chapter 9 F3C

½194


H3C N

C

R F3C

Figure 9.81

C6F6

+

C6F5N3

N3CN

i

45⬚ C

F

[C6F5N:]

½195


NC

N

½196


F N

i,

Flash Vac. Pyrolysis/300⬚ C N F

F N

Figure 9.82 CN

F

CN

hν

N3

F

CN c-C6H12

½197


F

N

N H

C6H11

75−80%

Figure 9.83 i C6F5Br

C6F5MgBr

CO2

C6F5COOH

½200


67%

i, Mg, Et2O, or THF

½201


O C6F5CH2CH2OH

Figure 9.84

Lithium derivatives [202] are more versatile and more convenient to use than the Grignard reagents, although the report of serious explosions occurring with pentafluoro-

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Polyfluoroaromatic Compounds

345

phenyl-lithium [203] emphasises the extreme care that must be taken. Although many and varied reactions using pentafluorophenyl-lithium and other polyfluoroaryl-lithiums have been carried out in the author’s laboratory, without incident, it is clear that all polyfluoroaryl-lithium or polyfluoroarylmagnesium derivatives should be treated as potentially hazardous, particularly when hydrocarbon solvents are used at low temperatures, at which the lithium derivative may be precipitated. In general, polyfluoroaryl-lithiums are best obtained by metal–halogen exchange [204] using, for example, commercially available butyl-lithium, or by metallation of hydro compounds [205–207], the hydrogen being especially acidic when flanked by two fluorine atoms. The latter method has the advantage of not generating alkyl bromides that can be difficult to separate from some products (Figure 9.85). C6F5Br

+

Et2O

n-BuLi

−78⬚ C

C6F5Li

H

F

+

n-BuBr

½204


Li Et2O

+ n -BuLi

F

½205, 208


−78⬚ C X

X X = H or F

Figure 9.85

The use of some polyfluoroaryl-lithiums in organic synthesis is illustrated in Table 9.9; these reagents have, of course, been used to make many corresponding derivatives of other elements, but this will be illustrated in the next chapter. Table 9.9 Some organic syntheses using polyfluoroaryl-lithiums Reaction

C6F5Li

Ref. i

C6F5OH

39%

[209]

i, B(OMe)3, H2O2 i, ii C6F5Li i, S8;

C6F5SH

46%

C6F5COOH

99%

[210]

ii, H2O i

C6F5Li

[205]

+

i, CO2; ii, H, Et2O, <55⬚ C

C6F5Li

HCO(NMe2)

C6F5CHO

61%

[211] Contd

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346

Chapter 9

Table 9.9 Contd (MeO)2CO

C6F5Li

(C6F5)2CO

OH

70%

OH

OLi

i, CO2

n-BuLi

F

F

F

+

ii, H

H

84%

Br

Br

Br H

F

F

H

H

ii

i Li

Br

H

Br

[207, 213]

HOMe2C

F

F

[209]

COOH

Li

F

[212]

+ (C6F5)3COH

Br F

i, LDA, THF, −78⬚ C; ii, Me2CO, −78⬚ C Li

H Cl

Cl

F

F

i N

H

COOH F

ii, iii H

F

Cl

N

F

[214] H

F F

+

i, LDA, THF, −78
C; ii, Me2CO, −78
C; iii, H

F

F

Li Li

SCl2

F

F

66%

[212]

S

Copper compounds [215]: An interesting contrast occurs between phenyl- and pentafluorophenyl-copper compounds, in that the fluorinated derivatives are considerably more stable [216–220] and are useful reagents in organic synthesis (Figure 9.86). A remarkable double insertion of difluorocarbene, derived from trifluoromethyl copper, has been reported [227] (Figure 9.87).

2 Arynes Polyfluoroaryl-lithiums and, to a lesser extent, the Grignard reagents will decompose by a b-elimination of metal fluoride, leaving an aryne whose properties are considerably affected by the remaining fluorine atoms. The highly electrophilic nature of these species leads to some reactions, e.g. with benzene derivatives, that are not shown by benzyne itself [228] (Figure 9.88).

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 347

Polyfluoroaromatic Compounds Monoglym e C6F5I

+

2Cu

C6F5MgBr

+

C6F5Cu

rt CuI

+

½221224


CuI

Dioxane

Et2O

½216, 219, 220


C6F5Cu.Dioxane

[C6F5Cu]

−Dioxane

130⬚ C PhI

C6F5C6H5

347

[C6F5Cu]4

87% MeI 200⬚ C C6F5Me 39% Cu(I)Cl, Mg

C6F5Cl

[C6F5Cu]

C6F5C6F5

MeCOCl

C6F5COMe

−5⬚ C

THF

72%

½225


CBr2=CHBr C6F5C i

C6F5Cl

C6F5Li

Cu(I)I

[C6F5Cu]

CC6F5

CF2=CFI

43%

½217


C6F5CF=CF2 55%

n-BuLi, THF, −70⬚ C

i,

C6F5Cu

+

CH2I2

½226


CH2(C6F5)2

Figure 9.86 C6F5Cu

+

−30⬚ C

CF3Cu

½227


C6F5CF2CF2Cu

DMF

Figure 9.87 X Li F

X

X S F

F

S X X

X = H, Cl −S

F

Figure 9.88

X

½228


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348

Chapter 9

In addition to these cycloaddition reactions with nucleophilic p-donors, tetrafluorobenzyne is very susceptible to more general nucleophilic attack. Biphenyl derivatives often occur as by-products in reactions of pentafluorophenyl-lithium, formed by addition to the benzyne [204, 229] (Figure 9.89). Li

H

Li C6F5Li

F

F

H

F

½204


F

C6F5

C6F5

Figure 9.89

A similar process, but involving further attack on the biphenyl and polyphenyls initially produced, may account for the high-molecular-weight materials formed in the decomposition of pentafluorophenylmagnesium bromide at elevated temperatures in THF solution [230, 231] (Figure 9.90). MgBr C6F5MgBr

C6F5MgBr

F

½230, 231
F

F

C6F5MgBr MgBr F

MgBr F

C6F5

F

F

C6F5

n

Figure 9.90

This type of process appears to occur even more easily with trifluoropyridyne [232] (Figure 9.91). Br

Li Furan

i F

F

F

N

N

N

i, n-BuLi, Et2O, −78⬚ C

½232


n-BuL i

Polymer

Figure 9.91

The addition of lithium pentafluorothiophenate to tetrafluorobenzyne leads to perfluorodibenzothiophene by a novel cyclisation [233] (Figure 9.92). Trapping with a 1,3-dipole has also been described [234] (Figure 9.93).

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Polyfluoroaromatic Compounds

F

F

i F

F

Br

SH

349

½233


S

i, n-BuLi, Et2O, C6H8, 0⬚ C

F

F

F

F

S

S

70%

Figure 9.92 Ph

H Li F

F

PhCH=N(Ph)O

N Ph

F

½234


O

Figure 9.93

Tetrafluorobenzyne may be involved in a number of other reactions, as outlined in Figure 9.94. The p-benzyne (9.94A) has been observed using matrix isolation techniques [236].

3

Free radicals

Free-radical aromatic substitutions were described earlier in this chapter (Section IID); the generation of polyfluoroaryl radicals may be achieved by conventional procedures and the effect of fluorine is mainly in making the radical more electrophilic in comparison with the hydrocarbon counterparts. This has been illustrated for pentafluorophenyl radicals in a quantitative fashion by competition for the radicals between chlorobenzene and benzene [237], giving kðC6 H5 Cl=C6 H6 Þ ¼ 0:72 in comparison with a value for phenyl radicals kðC6 H5 Cl=C6 H6 Þ ¼ 1:06. This lower relative rate for pentafluorophenylation, coupled with a greater tendency towards ortho, para substitution than with phenyl, is a quite clear indication of the electrophilic character of the fluorocarbon radical. This is also clear from other substituent effects, e.g. the greater proportion of meta substitution with nitrobenzene shown in Figure 9.95. Other reactions involving polyfluoroaryl radicals are shown in Figure 9.96. Thermal reactions of iodo compounds provide some useful direct syntheses of various sulphur and selenium compounds [240, 241], presumably involving radicals, and radicals are also produced from iodo derivatives by photolysis [242] (Figure 9.97). The photo-reduction of perfluorobenzophenone in isopropanol [243] provides an interesting contrast with the classical reduction of benzophenone to benzopinacol under the same conditions (Figure 9.98). This difference between the two systems has been attributed to the greater resonance stabilisation of the radical 9.98A in comparison with 9.98B and to electron-pair repulsions inhibiting the dimerisation of 9.98A.

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350

Chapter 9

F

O Hg O F

Hg

300⬚ C F

O

83%

Hg

½155


Hg O

F

F Hg Ag F

Hg

F

F

~255⬚ C

39%

½155


Hg F

O 750⬚ C

O

F

F

F

24%

½235


0.6mmHg O I i F

F

½236


9.94A I

i, hν, Ne matrix, 3K

Figure 9.94

C6F5NH2

+

C5H11ONO

C6F5

C6F5

+

C6H5CH3

C6F5 C6H4CH3

½237


o-(62.1), m-(21.5), p-(16.4)% C6F5

+

C6H5NO2

C6F5 C6H4NO2 o-(20.8), m-(53.4), p-(25.8)%

Figure 9.95

Pentafluorophenol is oxidised by lead tetra-acetate, giving products arising from intermediate C6 F5 O radicals [244, 245] (Figure 9.99).

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 351

Polyfluoroaromatic Compounds

i

½198


C6F5C6H5

C 6F5NHNH2

351

i, Bleaching Powder, C6H6

i

C6F5COCl

(C6F5COO)2

i, NaOH, H2O2;

ii

½238, 239


C6F5COOH + C6F5C6F5 + C6F5COOC6F5

ii, C6H6, 80⬚ C

Figure 9.96 S, 230⬚ C C6F5I

(C6F5)2S I

S S, 250⬚ C

F

½241


70%

I

½241


60%

F

F S

C6F5

½242


hν

C6F5I

70% Me

N

CH3CN Me

Me

N

H

Me

H

Figure 9.97

hν

(C6F5)2CO

HO (C6F5)2OH

Me2CHOH

F

C

etc

½243


C6F5

9.98A

Me2CHOH

(C6F5)2CHOH

cf

(C6H5)2C=O

(C6H5)2COH 9.98B

+ Ph Ph HO

Me2CO Ph Ph OH

Figure 9.98

4

Valence isomers [246–248]

Photochemistry of fluorinated aromatic systems has made an important contribution to the study of valence isomers because it has been possible to isolate and characterise some species on which there had previously only been speculation. Some of these, as might be expected, are very unstable (sometimes, treacherously so) towards reverting to

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352

Chapter 9 O

½244


O F

i

C6F5OH

i, ii, iii,

C6F5O

ii F F

Pb(OAc)4 Dimerisation C6F5O etc.

F

OC6F5

OC6F5 iii

O F F

OC6F5

C6F5O

Figure 9.99

the corresponding aromatic form. This is the case with perfluorobenzene but, when perfluoroalkyl groups are present, valence isomers have been isolated that are remarkably stable and thus present some fascinating systems to organic chemistry. Let us consider the possible effects of fluorine or fluorocarbon groups as substituents on the transformation of a benzene derivative to a para-bonded species 9.100A, a benzvalene 9.100B or a prismane 9.100C (Figure 9.100). X6 +

X6

9.100A

X6

9.100B

+ X6 9.100C

X = F or perfluoroalkyl

Figure 9.100

We established in Chapter 7, Section IIA, that fluorine prefers to be attached to saturated carbon and it is useful to recall the greater heat of polymerisation of tetrafluoroethene than ethene (by about 73 kJmol1 ). In the same way, fluorine in a benzenoid system may encourage the formation of 9.100A–C, where unsaturation is progressively decreasing. The most obvious effect of a perfluoroalkyl group is to increase the crowding. This is not necessarily relieved in the valence isomers and indeed it could be increased, since C–C–C bond angles are reduced from 1208, in the aromatic form, when the valence isomer is formed. However, crowding could have a profound effect on the the resonance energy of the aromatic isomer by reducing planarity, whereas no such consideration applies to the valence isomers 9.100A–C. Activation energies of reversion to the aromatic isomer vary in the range 96  128 kJmol1 [249] but the enthalpy changes DH for photoisomerisation are much more varied, e.g. 214 [C6 F6 ], 117 [C6 ðCF3 Þ6 ] and 35 kJmol1 ½C6 ðC2 F5 Þ6
. It appears that the thermal stability of valence isomers increases with the number of perfluoroalkyl substituents. Not the least advantage of fluorocarbon

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Polyfluoroaromatic Compounds

353

systems is the stability of carbon–fluorine bonds. In this sense fluorine or fluorocarbon groups are useful as ‘passive’ substituents [192], where skeletal rearrangements are being observed, in order to obtain a minimum of side-reactions. t-Butylfluoroacetylene is an extremely reactive compound that undergoes thermal oligomerisation, giving a benzene derivative and valence isomers [250] (Figure 9.101).

F (CH3)3CC

CF

F

+

F

F

½250


+ F

F

F ∆

∆

F

Figure 9.101

The para-bonded isomer of perfluorobenzene may be formed by irradiation, in the vapour phase, using 254 nm radiation [251–254] (Figure 9.102). Substituted benzenes, C6 F5 XðX ¼ H, CH3 , CF3 , OCH3 Þ [255], and trifluorobenzenes, C6 H3 F3 [256], all form para-bonded species on irradiation. hn F

F6

½254


Figure 9.102

Valence isomer 9.103A undergoes various reactions as a strained fluoroalkene (Figure 9.103). Very stable valence isomers have been isolated by irradiation of hexakis(trifluoromethyl)benzene and hexakis(pentafluoroethyl)benzene [257–259] in the gas phase or in solution. The sequence of formation of the isomers is shown in Figure 9.104. Kinetic and thermodynamic data for valence isomers have been compared [249, 260]. The bicyclopropenyl isomer (Figure 9.105) has been prepared by a carbene addition process; therefore, this system is quite unique in that all of the valence isomers are known and fully characterised. Nitrogen derivatives: A remarkable series of transformations has been discovered with fluorinated pyridazines, giving pyrimidines and small amounts of pyrazines on pyrolysis [262, 263] and pyrazines on photolysis [264]. Highly specific substituent labelling occurs on pyrolysis and diazabenzvalenes, or vibrationally excited species approaching these,

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354

Chapter 9 F6

F5

F4

MeO

OMe

OMe

NaOMe

½254


+

9.103A F6

F6

Br2

½254


Br Br

9.103A F6

COOH

O3

F

H2O

9.103A

O P2O5

F

O

COOH

½248


O i, ii

i

i, hν ii, hν, furan

F

O F

Figure 9.103

170⬚ C t1/2 9hr (CF3)6

<270nm

½258, 259


>200nm

(F3C)6

>200nm 170⬚ C t1/2 135hr (CF3)6 >200nm

(CF3)6 170⬚ C t1/2 129hr

Figure 9.104

F3C CF3C

CCF3

+

C Cl

Figure 9.105

N N

(CF3)3

(CF3)3

½261


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Polyfluoroaromatic Compounds

355

have been suggested [192] in order to account for the results, although no valence isomers have actually been isolated. Cycloaddition processes have been ruled out by N-15 labelling experiments. Furthermore, rearrangement is encouraged by free-radical promotors, leading to the conclusion that these processes involve free-radical-promoted formation of diazabenzvalene derivatives [263] (Figure 9.106). RF

RF N F

RF N

R

F RF

RF

N F

N

N

R

½263


N

RF

R −R

RF

RF

N

N

F N

F RF

RF

N

F

N

N

RF

RF

Figure 9.106

The situation is quite different in the photolysis reactions, where valence isomers of an aromatic diazine have been isolated, together with the pyrazines (Figure 9.107). From the structures of the isolated and characterised valence isomers, and the highly specific substituent labelling, a very unusual mechanistic pathway may be drawn as indicated in Figure 9.108. This appears to be the first case where substituent labelling has allowed each stage in a photochemical aromatic rearrangement to be identified through various intermediate valence isomers. RF

F F

RF

N

254nm gas phase N RF

F

N

N

RF

F

i

RF

i

RF N

+

N

N

RF

RF

F

F

F

F

½264, 265


i = hν or heat RF

F RF

F N N

F

254nm gas phase

RF i

F N

F N

+

N

N

RF

RF F

RF

i = hν or heat RF = F , CF(CF3)2 , CF2CF3 , CF(CF3)(C2F5)

Figure 9.107

½264, 265


N

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 356

356

Chapter 9 3

4

4

N

2

5

N

1

N

1

3

N

6

2

5

6

3

3

4

4

N

2

4

N

2

5

N

1

5

N

1

1

N

6

3

N

5

2

6

6

9.108A

Figure 9.108

Some of the valence isomers (e.g. 9.108A) have a half-life of a few minutes at 1008C. In contrast, valence isomers of some polyfluorinated pyridine derivatives have substantial stability [266] (Figure 9.109). N

>200nm N

(CF3CF2)5

270nm

N

>200nm

½266


(CF3CF2)5

(CF3CF2)5

Figure 9.109

Again, substituent labelling studies have enabled photochemical rearrangement mechanisms to be clearly associated with the intermediate valence isomers, in this case involving azaprismane derivatives (Figure 9.110). Rearrangement a

a b

b

hν

c

c

N

b c

x c b

b +

N

xN y

c

c

y

x a b a

b +

x N

c

½267


b c

heat heat cleavage, y

heat cleavage, x b b c

N

heat cleavage, x

b c

b

a

c N

b a

b

c

a

c N

c

a = CF3CF2-; b = CF3-; c = (CF3)2CF

Figure 9.110

In some cases, photochemically induced eliminations occur; in the case of fluorinated 1,2,3-triazines, this has generated azetes [268, 269] which have been trapped and even observed by low-temperature isolation techniques [269] (Figure 9.111).

Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 357

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357

Adduct ii F RF N

RF

F

RF

RF

RF

F

½268, 269


N

i N

N

N

RF

N

F

RF

RF iii

RF RF F

RF

N F F

−RFCN N

RF

F

RF

RF

RF

F N

RF

N

RF

RF

N

F RF

i = hv; ii = furan; iii = 350⬚ C RF = CF(CF3)2

Figure 9.111

Thermal elimination of nitrogen presents a route to fluorinated alkyne derivatives [270] (Figure 9.112). Y X N

∆

XC

½270


CY

N X Y X = Y = C6F5 (90%); X = CF3CF2; Y = C6F5

88%

Figure 9.112

Dewar thiophene (9.113A) and, from this, Dewar pyrrole derivatives have been isolated [246]. In contrast, photolysis of furan derivatives only promoted cyclopropenyl ketone rearrangements [271] (Figure 9.113). i S

(CF3)4

(CF3)4

ii

S

(CF3)3 O

ii,

S

heat or Pd Catalyst

hν

X

(CF3)3 X O

X = F or CF3

Figure 9.113

½246


F3C

9.113A i, hν;

(CF3)3

½271


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153 V.D. Shteingarts, G.G. Yakobson and N.N. Vorozhtsov, Dokl. Acad. Nauk SSSR, 1966, 170, 1348. 154 V.D. Shteingarts in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and G.K.S. Prakash, John Wiley and Sons, New York, 1992, p. 259. 155 P. Sartori and A. Golloch, Chem. Ber., 1968, 101, 2004. 156 V.D. Shteingarts, Y.V. Pozdnyakovich and G.G. Yakobson, J. Chem. Soc., Chem. Commun., 1969, 1264. 157 V.D. Shteingarts and Y.V. Pozdnyakovich, Zhur. Org. Khim., 1971, 7, 734. 158 N.M. Bazin, N.E. Akhmetova, L.V. Orlova, V.D. Shteingarts, L.N. Shchegoleva and G.G. Yakobson, Tetrahedron Lett., 1968, 4449. 159 T.J. Richardson, F.L. Tanzella and N. Bartlett, J. Am. Chem. Soc., 1986, 108, 4937. 160 K. Zuchner, T.R. Richardson, O. Glemser and N. Bartlett, Angew. Chem., Int. Ed. Engl., 1980, 19, 944. 161 V.A. Petrov in Organofluorine Chemistry: Fluorinated Alkenes and Reactive Intermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 39. 162 W.F. Beckert and J.U. Lowe, J. Org. Chem., 1967, 32, 1212. 163 E. Nield, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1959, 166. 164 P.L. Coe, A.E. Jukes and J.C. Tatlow, J. Chem. Soc. (C), 1966, 2323. 165 P.L. Coe and A.E. Jukes, Tetrahedron, 1968, 24, 5913. 166 A. Orlinkov, I. Akrem, S. Vitt and M. Vol’pin, Tetrahedron Lett., 1996, 37, 3363. 167 P.L. Coe, G.M. Pearl and J.C. Tatlow, J. Chem. Soc. (C), 1971, 604. 168 R.D. Chambers and D.J. Spring, J. Organometal Chem., 1971, 31, C13. 169 L.S. Kobrina, J. Fluorine Chem., 1989, 42, 301. 170 J.A. Godsell, M. Stacey and J.C. Tatlow, Nature, 1956, 178, 199. 171 R.E. Banks, W.M. Cheng, R.N. Haszeldine and G. Shaw, J. Chem. Soc. (C), 1970, 55. 172 P.A. Claret, G.H. Williams and J. Coulson, J. Chem. Soc. (C), 1968, 341. 173 G.H. Williams, Intra-Science Chem. Reports, 1969, 3, 229. 174 P.H. Oldham, G.H. Williams and B.A. Wilson, J. Chem. Soc. (B), 1970, 1346. 175 H. Sawada, Chem. Rev., 1996, 96, 1779. 176 A.G. Hudson, M.L. Jenkins, A.E. Pedler and J.C. Tatlow, Tetrahedron, 1970, 26, 5781. 177 A.G. Hudson, A.E. Pedler and J.C. Tatlow, Tetrahedron, 1970, 26, 3791. 178 C.M. Jenkins, A.E. Pedler and J.C. Tatlow, Tetrahedron, 1971, 27, 2557. 179 R.D. Chambers, D.T. Clark, C.R. Sargent and F.G. Drakesmith, Tetrahedron Lett., 1979, 20, 1917. 180 V.I. Krasnov, V.E. Platonov, I.V. Beregovaya and L.N. Shchegoleve, Tetrahedron, 1997, 53, 1797. 181 S.S. Laev and V.D. Shteingarts, Tetrahedron Lett., 1997, 38, 3765. 182 M. Jones, J. Org. Chem., 1968, 33, 2538. 183 D.M. Gale, J. Org. Chem., 1968, 33, 2536. 184 V.E. Platonov, N.V. Ermolenko, G.G. Yakobson and N.N. Vorozhtsov, J. Gen. Chem. USSR, 1968, 2606. 185 N.N. Vorozhtsov, N.V. Ermolenko, S.A. Mazalov, O.M. Osina, V.E. Platonov, V.S. Tyurin and G.G. Yakobson, J. Gen. Chem. USSR, 1969, 195. 186 V.E. Platonov and G.G. Yakobson, Soviet Scientific Reviews, Section B, Chem. Rev., 1984, 5, 297. 187 V.E. Platonov, G.G. Furin, N.G. Malyuta and G.G. Yakobson, Zh. Org. Khim., 1972, 8, 430. 188 N.G. Malyuta, V.E. Platonov, G.G. Furin and G.G. Yakobson, Tetrahedron, 1975, 31, 1201. 189 V.E. Platonov, N.V. Ermolenko and G.G. Yakobson, Bull. Acad. Sci. USSR, 1970, 2685. 190 T.D. Petrova, V.E. Platonov, M.I. Gorfinkel, I.S. Isaev and G.G. Yakobson, J. Org. Chem., USSR, 1971, 7, 1311. 191 R.E. Banks, D.S. Field and R.N. Haszeldine, J. Chem. Soc. (C), 1970, 1280. 192 R.D. Chambers, J.A.H. MacBride and W.K.R. Musgrave, J. Chem. Soc. (C), 1971, 3384.

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Polyfluoroaromatic Compounds

193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235

363

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236 H.H. Wenk, A. Balster, W. Sander, D. Hrovat, W.T. Borden and T. Weston, Angew. Chem., Int. Ed., 2001, 40, 2295. 237 P.H. Oldham, G.H. Williams and B.A. Wilson, J. Chem. Soc. (B), 1971, 1094. 238 J. Burdon, J.B. Campbell and J.C. Tatlow, J. Chem. Soc. (C), 1969, 822. 239 P.H. Oldham and G.H. Williams, J. Chem. Soc. (C), 1970, 1260. 240 S.C. Cohen, M.L.N. Reddy and A.G. Massey, J. Chem. Soc., Chem. Commun., 1967, 451. 241 S.C. Cohen, M.L.N. Reddy and A.G. Massey, J. Organometal. Chem., 1968, 11, 563. 242 Q.-Y. Chen and Z.-T. Li, J. Chem. Soc., Perkin 1, 1993, 1705. 243 N. Filipescu, J.P. Pinion and F.L. Minn, J. Chem. Soc., Chem. Commun., 1970, 1413. 244 L.S. Kobrina, V.N. Kovtonyuk and G.G. Yakobson, Zh. Org. Khim., 1977, 13, 1447; Chem. Abstr., 1977, 87, 151814r. 245 V.N. Kovtonyuk, L.S. Kobrina and G.G. Yakobson, Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk, 1984, 2, 119. 246 Y. Kobayashi and I. Kumadaki, Acc. Chem. Res., 1981, 14, 76. 247 D. Lemal in Fluorine Chemistry at the Millennium, ed. R.E. Banks, Elsevier, Amsterdam, 2000, p. 297. 248 D. Lemal, Acc. Chem. Res., 2001, 34, 662. 249 B. Sztuba and E. Ratajzak, J. Chem. Soc., Perkin Trans. 2, 1982, 823. 250 H.G. Viehe, Angew. Chem., Int. Ed. Engl., 1965, 4, 746. 251 G. Camaggi, F. Gozzo and G. Cevidalli, J. Chem. Soc., Chem. Commun., 1966, 313. 252 I. Haller, J. Am. Chem. Soc., 1966, 88, 2070. 253 I. Haller, J. Chem. Phys., 1967, 47, 1117. 254 G. Camaggi and F. Gozzo, J. Chem. Soc. (C), 1969, 489. 255 P. Cadman, E. Ratajczak and A.F. Trotman-Dickenson, J. Chem. Soc. (A), 1970, 2109. 256 G.P. Semeluk and R.D.S. Stevens, J. Chem. Soc., Chem. Commun., 1970, 1720. 257 M.G. Barlow, R.N. Haszeldine and R. Hubbard, J. Chem. Soc., Chem. Commun., 1969, 202. 258 D.M. Lemal, J.V. Staros and V. Austel, J. Am. Chem. Soc., 1969, 91, 3374. 259 M.G. Barlow, R.N. Haszeldine and R. Hubbard, J. Chem. Soc. (C), 1970, 1232. 260 D.M. Lemal and L.H. Dunlap, J. Am. Chem. Soc., 1972, 94, 6562. 261 M.W. Grayston and D.M. Lemal, J. Am. Chem. Soc., 1976, 98, 1278. 262 R.D. Chambers, M. Clark, J.R. Maslakiewicz, W.R.K. Musgrave and P.G. Urben, J. Chem. Soc., Perkin Trans. 1, 1976, 1513. 263 R.D. Chambers, W.K.R. Musgrave and C.R. Sergent, J. Chem. Soc., Perkin Trans. 1, 1981, 1071. 264 R.D. Chambers, J.A.H. MacBride, J.R. Maslakiewicz and K.C. Srivastava, J. Chem. Soc., Perkin Trans. 1, 1975, 396. 265 R.D. Chambers, J.R. Maslakiewicz and K.C. Srivastava, J. Chem. Soc., Perkin Trans. 1, 1975, 1130. 266 M.G. Barlow, J.G. Dingwall and R.N. Haszeldine, J. Chem. Soc., Chem. Commun., 1970, 1580. 267 R.D. Chambers and R. Middleton, J. Chem. Soc., Perkin Trans. 1, 1977, 1500. 268 R.D. Chambers, T. Shepherd and M. Tamura, J. Chem. Soc., Perkin Trans. 1, 1990, 975. 269 R.D. Chambers, T. Shepherd, M. Tamura and P. Hoare, J. Chem. Soc., Perkin Trans., 1, 1990, 983. 270 R.D. Chambers, M. Clark, J.A.H. MacBride, W.K.R. Musgrave and K.C. Srivastava, J. Chem. Soc., Perkin Trans. 1, 1974, 125. 271 R.D. Chambers, A.A. Lindley and H.C. Fielding, J. Fluorine Chem., 1978, 12, 337.

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Chapter 10

Organometallic Compounds

Organometallic compounds have been referred to at various points in this book and their role as reactive intermediates, where significant, has been outlined. Frequent comparisons have been made between the chemistry of functional-hydrocarbon and corresponding functional-fluorocarbon systems with the aim of building up a picture of the effect of fluorine as a substituent on the chemistry of various functional groups, reactive centres and the like. Needless to say, a similar consideration of the effect of fluorine on the properties of carbon–metal bonds is fascinating in itself and, over the years, striking developments in this novel field of organometallic chemistry have been made. This book is about organic chemistry and it cannot cover this field of inorganic chemistry as a whole. What follows, therefore, is a discussion of systems that are largely of interest to, or useful to, the organic chemist. There are a number of reviews available [1–19], and other key references will be given in the text. The earliest and still one of the most dramatic contrasts between hydrocarbon and the corresponding fluorocarbon organometallic systems is that between dimethyland bistrifluoromethyl-mercury [20]. The latter is a white crystalline solid (melting point 1638 C) that is slightly soluble in water, whereas dimethylmercury is a covalent liquid (boiling point 928 C). In a less dramatic but more useful way, transition-metal compounds [21] are generally more thermally stable with fluorocarbon groups attached. Attached fluorocarbon groups often enhance the acceptor properties of a metal and the metal generally becomes more susceptible to nucleophilic attack. The converse also applies: that is, electrophilic attack becomes more difficult, especially in cases where a metal is attached only to perfluoroalkyl or perfluoroaryl groups, although the situation is more complicated with mixed derivatives.

I

GENERAL METHODS OF SYNTHESIS

It will become clear that, in some cases, the classical routes to organometallics are not available but, compensating for this, the different chemistry of, for example, unsaturated fluorocarbons has often been exploited to provide quite new synthetic approaches.

A 1

From iodides, bromides and hydro compounds Perfluoroalkyl derivatives

Fluorocarbon organometallic chemistry began with the first syntheses of perfluoroalkyl iodides (see Chapter 7, Sections IIC, Subsection 7, and IIE, Subsection 2, for current methods). On the basis of classical methods, this might have been expected to lead logically to the corresponding lithio derivatives and these, in turn, to a considerable Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

365

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366

Chapter 10

array of perfluoroalkyl derivatives of other elements. However, perfluoroalkyl-lithiums, as well as the corresponding magnesium compounds, too readily undergo elimination of metal fluoride; although the route has been used in some cases, the method is inevitably seriously restricted (Figure 10.1). n-C4H9Li

+

i

i-C3F7I

i-C3F7Li

+

½22


n-C4H9I −LiF

CF3CF=CF2 i CH3Li + C2F5I

ii

[C2F5Li]

C2F5C(OH)PhCH3 +

i, Et2O, −78
C

ii, PhCOCH3, H

88%

½23


etc.

Figure 10.1

A warning has been given [24] about carrying out exchange reactions to form pentafluoroethyl-lithium at very low temperatures, where violent decomposition has been observed. The most likely explanation for these events is that solid perfluoroethyllithium is precipitated at the low temperature and, of course, this is extremely unstable with respect to formation of the metal fluoride. The same cautionary note may be made for all fluorinated alkyl- or aryl-lithium compounds (see Chapter 9, Section IIE, Subsection 1) The carbon–iodine bond in perfluoroalkyl iodides is usually susceptible to homolytic fission; this was exploited in early work on the synthesis of mercurials and in later work relating to group IVB and transition-metal derivatives (Figure 10.2).

CF3I + Hg

∆

½20


CF3HgI hν

(CH3)3SnSn(CH3)3 + CF3I

(CH3)3SnI + (CH3)3SnCF3

½25


Figure 10.2

2 Derivatives of unsaturated systems Perfluoropropynyl [15, 26, 27] and perfluorovinyl [16, 28–30]-lithium and -magnesium are considerably more stable than perfluoroalkyl derivatives, whilst the corresponding perfluoroaryl derivatives may be used as effectively as in the hydrocarbon series, and direct syntheses involving iodo compounds are also possible (Figure 10.3). This quite definite trend towards increasing stability in a series from CF3 Li, which may have little more than a fleeting existence when generated, to RF LiðRF 5C2 F5 , n- and i-C3 F7 ), CF5CFLi and C6 F5 Li is probably a reflection of the ease of elimination of metal fluoride decreasing in this series; see also Chapter 6, Sections II and IIIA, Subsection 3 (Figure 10.4).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 367

Organometallic Compounds i

CF3CH2CF2H

[CF3CH=CFH]

(−LiF) i, n-BuLi;

i

[CF3C

CH]

367

½27


(−LiF) i

ii, Ph3SnCl Ph3SnC

ii

CCF3

CF3C

CLi

84% i

CF3CFH2

i

[CF2=CFH]

CF2=CFLi

½30


(−LiF) +

i, n-BuLi;

ii

etc.

ii, PhCHO, H

PhCH(OH)CF=CF2 n-BuLi

C6F5H

i

C6F5I

HgCl2

C6F5Li

(C6F5)2Hg

(C6F5)2M

M = Zn or Cd

½11
½11


i, Zn (200
C) or Cd (230
C)

Figure 10.3 −LiF

CF3Li

CF2=CFLi

−LiF

[ CF2]

[CF

etc

CF]

or

[CF2=C ]

Li F

−LiF

F

Figure 10.4

B

From unsaturated fluorocarbons

The most obvious feature of the chemistry of highly fluorinated aromatic compounds and alkenes which can be exploited is their susceptibility to nucleophilic attack. Therefore, reactions with anionic species containing metals can be useful and the most significant examples of this type involve transition-metal carbonyl anions [6, 10] (Figure 10.5).

1

Fluoride-ion-initiated reactions

Reactions which partly compensate for the unsuitability of the perfluoroalkyl-lithium route involve addition of fluoride ion to an unsaturated site giving corresponding carbanions (Cs or K derivatives) that may be used in synthesis (see Chapter 7, Section IIC,

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368

Chapter 10 F

+

[Re(CO)5]

−

½6


F Re(CO)5

N

[πC5H5Fe(CO)2]

N

½6


N

−

+

F

F

N Fe(CO)2πC5H5

Figure 10.5

Subsection 6). Mercurials have been obtained by fluoride-ion-initiated reactions of perfluoroalkenes with mercury(II) chloride [31], and it is probable that the process could be extended considerably (Figure 10.6). −

F

i

−

+ CF2=CFCF3

(CF3)2CF

Hg[CF(CF3)2]2

½31


i, HgCl2

Figure 10.6

II LITHIUM AND MAGNESIUM A From saturated compounds Some polyfluoroalkyl-lithium and polyfluoroalkyl-Grignard reagents have been described [14] but, as already mentioned, elimination of metal fluoride seriously restricts the use of these compounds in synthesis. Perfluoroalkylmagnesium reagents are prepared either directly from perfluoroalkyl iodides and magnesium, or by exchange between perfluoroalkyl iodides and a Grignard reagent, but perfluoroalkyl-lithiums can only be made by an exchange process. Typical reactions of these reagents are given in Figure 10.7. i

i-C3F7Li

CF3CF=CF2

i, H2SO4, Et2O i

i-C3F7Li

N.B.

Little or no i-C3F7H formed

½22


66%

EtCH(i-C3F7)OH

½22


53%

i, EtCHO, H2SO4 ICF2CF2I

+

i, ii

[n-C4F9Li + MeCHO] i, −80
C to −85
C

[MeCH(OH)CF2-]2

½32


+

ii, H

Figure 10.7

The fact that exchange occurs to produce, in each case, the fluorocarbon derivative is quite consistent with the general observation that exchange generally proceeds to give a product where the metal is bonded preferentially to the most electronegative group [33].

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Organometallic Compounds

369

The perfluoro-n- and -i-propyl and -n-heptyl derivatives [22, 34–36] are the most stable of the simple alkyl series. Outstandingly different in character from the perfluoroalkyl derivatives described above are the lithium and magnesium compounds derived from highly fluorinated bicyclo[2.2.1]heptanes [37, 38]. Some reactions of the lithio derivative are shown in Figure 10.8, illustrating that it can be utilised in the normal synthetic procedures with much less competition from elimination.

MeLi

F

D2O

F

Et2O, −40
C Li

H

D

Furan I2

½37


F

i, MeCHO

MeI

+

ii, H

F 10.8A

F I

F Me

F CH(OH)Me

F O

Figure 10.8

This difference is obviously due to the difficulty in producing a double bond at a bridgehead position. Nevertheless, elimination of lithium fluoride does occur, especially at reflux temperatures; the bridgehead alkene 10.8A, which probably has only a transitory existence or may even be more appropriately described as a diradical, may be trapped with furan.

B

From alkenes

Several perfluoroalkene derivatives have been made and used successfully in synthesis. Trifluorovinylmagnesium bromide and the lithium derivative may be obtained [39–41] from bromotrifluoroethene but preparation from HFC 134a, which involves metallation of trifluoroethene generated in situ, is now the more accessible route (see Section IA). However, direct metallation of fluorinated alkenes and fluorinated cycloalkenes has also been reported [26, 28] (Figure 10.9).

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370

Chapter 10 i

CF2=CFBr

CF2=CFMg

H2SO4

CF2=CFH

43%

½40


i, Mg + I2, THF, ~ −22
C i Me2SnCl2

+

65%

½42


CF2=CFLi + C4H10

½28


Me2Sn(CF=CF2)2

Mg

i, CF2=CFBr, THF, 0
C CF2=CFH + n-BuLi

i

i, Et2O or THF, −78
C ii, CO2

ii iii

iii, H+

CF2=CFCOOH H F

65%

½26


Li + MeLi

(CF2)n

Et2O −70
C

F

CH4 + (CF2)n

i, MeCHO ii, H+

n = 1, 23% n = 2, 42% n = 3, 63%

CH(OH)Me F (CF2)n

Figure 10.9

C From trifluoropropyne [15] The C2H bond in trifluoropropyne is sufficiently acidic to allow ready metallation via Grignard or lithium reagents (Figure 10.10). However, the route from CF3 CH2 CF2 H [27] (Section IA, Subsection 2) is more direct. i CF3C

CH

+

n-BuLi

C4H10

+

CF3C

i, C5H10, Et2O, −78
C

CLi

½43


Et3SiCl Et3SiC

CCF3

Figure 10.10

A number of derivatives of metals have been synthesised [15]; the lithium and magnesium derivatives, especially, are capable of quite wide application.

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Organometallic Compounds

D

371

From polyfluoro-aromatic compounds [7, 17, 18, 21]

The generation of Grignard reagents and lithium derivatives was discussed in Chapter 9, Section IIE, Subsection 1, and these reagents have already provided an impressive number of derivatives, which are discussed in detail in reviews [7, 17, 18, 21]. Some examples are shown in Figure 10.11 but more will be found in the following text. The steric requirements of the ligands in 10.11A are considerable and this feature has allowed a number of unusual systems to be synthesised [48]. i

C6F5MgBr

(C6F5)4Si

½44


i, SiCl4, Et2O i

C6F5MgBr

(C6F5)2Hg

½45


73%

i, HgCl2, Et2O

½46
C6F5Li

i

(C6F5)3B

50%

i, BCl3, Pentane/Hexane, −78
C to rt CF3

CF3 F3C

n-BuLi

F3C

CF3

CF3 Li

MX2

F3C

M

CF3 M = Zn, Cd, Hg.

½47, 48


CF3

2

10.11A

Figure 10.11

Metallation of less highly fluorinated systems has been reviewed [49].

III

ZINC AND MERCURY

A

Zinc

Less work had been done with zinc compounds, but enough to indicate a contrast with lithium and magnesium derivatives. For example, perfluoro-n-propyl zinc iodides [50, 51] and perfluoroisopropyl zinc iodides [22] can be obtained, and the n-propyl derivative is even stable in dioxane at reflux. It should be noted that these compounds are stable largely because they are solvated and it has not been possible to remove the solvent completely. Zinc under these circumstances appears to be a very strong acceptor and therefore the compounds decompose much more readily when formed in the free state [52] (Figure 10.12). Ultrasonic radiation of perfluoroalkyl iodides may be used to form zinc reagents which undergo standard reactions (Figure 10.13). Fluorovinylzinc reagents are especially useful [14] (Figure 10.14).

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372

Chapter 10

i

n-C3F7I

~155
C

n-C3F7ZnI

i, Zn, Dioxane, 100
C, ii, Removal of Solvent

CF3CF=CF2

½51


ii

n-C3F7ZnI/dioxane

n-C3F7COCl

(n-C3F7)2CO 15%

i

n-C3F7I

ii

n-C3F7ZnI

½50


n-C3F7ZnI/dioxane

i, Zn, Dioxane, 100
C, ii, Removal of Solvent

H2O

100
C

n-C3F7H

96%

Figure 10.12 Ph C3F7I

Ph

i

+

½53


66%

Br

C3F7 i, Pd(Ph3P)4, Zn, THF

Ph C3F7I

Ph

i

+

71%

Br

½53


C3F7 i, Pd(Ac)2, Zn, THF CF3I

+

HOCH2C

i

CH

CF3CH=CHCH2OH

½53


61%

i, CuI, Zn, THF C2F5I

i

+

½53


51% C2F5

i, Cp2TiCl2, Zn, THF CF3I

+

PhCHO

Zn DMF

PhCH.OHCF3

72%

½53


OH CF3CCl3 +

PhCO

Zn DMF

½54


86% Ph

CCl2CF3

Figure 10.13

CF2=CFBr

Figure 10.14

Zn DMF

[CF2=CFZnBr]

Me3SiCl

CF2=CFSiMe3

65%

½55


Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 373

Organometallic Compounds

373

Perfluoroarylzinc derivatives may be obtained directly from the corresponding iodide and, sometimes, the chloride; they are also sufficiently stable to be produced by decarboxylation procedures (Figure 10.15). C6F5I

+

Zn

½14
C6F5Li

+

ZnCl2

(C6F5)2Zn

(C6F5CO2)2Zn

ZnCl

Cl F

F

N

N

½56
25%

Figure 10.15

Surprisingly, zinc has been inserted directly into C2F bonds using ultrasound techniques, and in the presence of metal salts, e.g. SnCl2 . The reactivity of the system appears to depend at least partly on the electron affinity of the aromatic system, because hexafluorobenzene is relatively unreactive in the process [57] (Figure 10.16). CF3

CF3

F

i

F

ZnCl

CF3 Br2

½57


F

Br

i, Zn, SnCl2, DMF, Ultrasound

Figure 10.16

B 1

Mercury Perfluoroalkyl derivatives

Perfluoroalkyl derivatives of mercury were the first fluorocarbon–organometallic compounds to be reported. Alkylmercurials are valuable in that they are able to alkylate other metals, but the toxicity of mercurials greatly inhibits the use of these systems. Perfluoroalkyl iodides react with mercury on heating or irradiation with ultraviolet light to give perfluoroalkylmercury(II) iodides [58–60] (Figure 10.17). An effective route to a number of bis(perfluoroalkyl)- and bis(perfluorocycloalkyl)mercurials involves fluoride-ion-induced reactions of fluoroalkenes [31]; this follows an earlier method involving addition of mercury(II) fluoride to fluoroalkenes, e.g. using anhydrous hydrogen fluoride as solvent [62] (Figure 10.18).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 374

374

Chapter 10

CF3I

+

80% (i)

i or ii

Hg

CF3HgI

½20


22% (ii) i, hν (150
C), or ii, ~275
C i

½61


(CF3)2Hg

(CF3COO)2Hg i, K2CO3, 120 to180
C

Figure 10.17

CF3CF=CF2

+

HgF2

i

[(CF3)2CF]2Hg

60%

½62


[(CF3)2CF]2Hg

65%

½31


[(CF3)3C]2Hg

66%

½31


i, Anhyd HF, 110
C CF3CF=CF2

+

HgCl2

i

i, KF, DMF, 40
C (CF3)2C=CF2

+

HgF2

i

i, KF, DMF, −78
C

Figure 10.18

2 Unsaturated derivatives Alkenyl [63], alkynyl [26], and aryl [7, 8, 11] derivatives can be obtained by standard procedures (Figure 10.19). CF2=CFLi

+

HgCl2

C6F5MgBr

+

HgCl2

COO

Et2O

(CF2=CF)2Hg

52%

½41


(C6F5)2Hg

73%

½45


Hg

Hg ∆

F N

Et2O

2

½64


F N

2

Figure 10.19

Pentafluorophenylmercurials can also be made by interesting direct mercuration procedures, e.g. with mercury(II) trifluoroacetate [65] and by a base-catalysed process [66] (Figure 10.20).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 375

Organometallic Compounds C6F5H + Hg(OCOCF3)2

150
C

C6F5HgOCOCF3

85%

½65


i

i, EtOH, NaI, rt

(C6F5)2Hg 2−

375

72% −

−

(C6F5)2Hg + 4Br

C6F5H + HgBr4 + 2 OH

+ 2H2O

½66


Figure 10.20

These polyfluoroaryl groups enhance the acceptor properties of mercury and neutral 1:1 coordination complexes can be isolated with bipyridyl, 1,2-bis(diphenylphosphino)ethane, 1,10-phenanthroline, and so on [45, 63]. Whereas bis(perfluoroalkyl)mercurials are cleaved by alkali, nucleophilic aromatic substitution occurs with bis(pentafluorophenyl)mercury [67] (Figure 10.21). (C6F5)2Hg + KOH

t-BuOH 100
C

(4-HOC6F4)2Hg

½67


Figure 10.21

Also, unlike bis(perfluoroalkyl)mercurials, bis(pentafluorophenyl)mercury may be used in a number of transformations at high temperature [68] (Figure 10.22). (C6F5)2Hg

(C6F5)2Hg

S 250
C Sn 260
C

(C6F5)2S

82%

½68


(C6F5)4Sn

60%

½68


Figure 10.22

3

Cleavage by electrophiles

Generally, polyfluoro-aromatic compounds and polyfluoroalkenes are not particularly susceptible to electrophilic attack and, consequently, electrophilic cleavage of these groups from metals, which in some cases occurs very rapidly, is of considerable interest. Unsymmetrical phenylpentafluorophenyl and methylpentafluorophenyl compounds are obtained from the appropriate mercury(II) halide [45], or by decarboxylation procedures [69], and these mixed derivatives are particularly susceptible to attack. Nevertheless, bis(pentafluorophenyl)mercury is very resistant to acid cleavage; for example, it can be recrystallised from concentrated sulphuric acid, but the well-known ligand-exchange process, e.g. with mercury(II) chloride, occurs very rapidly and presumably by a fourcentre process [45] (Figure 10.23). An order of susceptibility to electrophilic attack may be formulated as C6 H5 > C6 F5 > C6 Cl5 > CH3 , which correlates with similar cleavage reactions of tin derivatives. These reactions have applications in the synthesis of boron and aluminium compounds.

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 376

376

Chapter 10

F (C6F5)2Hg

+

2 C6F5HgCl

HgCl2 C6F5Hg Cl

δ+ HgCl δ−

HCl (g) C6F5HgCH3

½45


C6F5H + CH3HgCl HCl (g)

C6F5HgC6H5

C6H6

½45


½45, 70


+ C6H5H (trace) + C6F5HgCl

Figure 10.23

IV

BORON AND ALUMINIUM

A Boron 1 Perfluoroalkyl derivatives A considerable effort was expended in attempting to prepare a compound with a perfluoroalkyl group attached to boron before success was achieved. Difficulty arises from the propensity of a fluorine atom for migration from carbon to boron; for example, the compound CF3 BF2 has been isolated in low yields [71, 72] and delightfully described as ‘enduringly metastable’, with respect to formation of BF3 . It is not clear, however, whether this decomposition is intermolecular (10.24A), intramolecular (10.24B) or both (Figure 10.24). F

F CF3BF2

F

C F

10.24A

BF2

or

F

C

BF2

F 10.24B

Figure 10.24

This ease of migration of fluorine from carbon to boron has inhibited the development of hydroboration techniques in fluorinated systems. However, when the carbon–fluorine bond is sufficiently remote from the boron, then hydroboration works well and Markovnikov or anti-Markovnikov additions may be obtained, depending on the hydroborating system; dicyclohexylborane, Chx Þ2 BH, is less electrophilic but sterically more demanding than dihaloboranes (Figure 10.25). At the root of the instability of fluoroalkylboron compounds is the availability of a vacant orbital on boron; it will be seen that when boron is co-ordinately saturated, as in four-covalent boron derivatives (10.26A), or partially saturated by p bonding with attached oxygen- or nitrogen-containing groups (10.26B), then the stability of perfluoroalkylboron compounds increases (Figure 10.26).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 377

Organometallic Compounds

iii, ii

OH

i,ii

½73, 74


RFCHOH.CH3

RF

RF 86% yield (RF = C6F13)

90% yield (RF = C6F13)

95% Regioselective

99% Regioselective

80% yield (RF = CF3)

82% yield (RF = CF3)

94% Regioselective

99% Regioselective

i,

377

HBCl2, Hexane; ii, H2O2, alkaline; iii, (Chx)2BH, THF

Figure 10.25

X B

X B

RF X

10.26A

RF

B

RF

X

10.26B X = O- or N<

Figure 10.26

Several salts containing the anion ½RF BF3
 ðe:g: RF ¼ CF3 , C2 F5 Þ have been isolated [75a], as indicated below, while the tri-covalent derivatives 10.27A and 10.27B are not readily decomposed; for example, 10.27A is recovered unchanged after heating to 1208 C. Furthermore, thermal decomposition of 10.27A or 10.27B gives n-C3 F7 H and not perfluoropropene, which would be formed if migration of fluorine to boron was still important [76] (Figure 10.27).

2

Unsaturated derivatives

There is a marked increase in stability, with respect to formation of boron trifluoride, along the series CF3 BF2  CF2 5CFBF2 < C6 F5 BF2 [71, 77, 78] and this can be related to partial co-ordinative saturation of boron. Trifluorovinylboron and pentafluorophenylboron halides are synthesised by electrophilic cleavage from unsymmetrical tin compounds or mercurials [7, 17, 18] (Figure 10.28). The formation of C6 F5 BF2 rather than ½C6 F5 BF3
 indicates that C6 F5 BF2 is a weaker Lewis acid than BF3 , i.e. CF3 BF2 > BF3 > C6 F5 BF2 . A complex salt 10.29A can, however, be obtained by addition of C6 F5 BF2 to an aqueous solution of potassium fluoride; the salt undergoes a novel elimination process on pyrolysis, giving polyphenylenes 10.29B [79] (Figure 10.29). Trifluorovinylboron derivatives are only stable for short periods when heated at 1008 C, and their partial decomposition to boron trifluoride occurs even on standing at room temperature [77, 80]. Heating pentafluorophenylboron difluoride leads to disproportionation and not aryne formation [78] (Figure 10.30).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 378

378

Chapter 10

i Me3SnCF3

aq. KF

Me3Sn(CF3BF3)

K(CF3BF3) + Me3SnF ∆

i, BF3, CCl4, −196 to −20
C CF2=CF2

F

+

F

+

[ CF2] + KBF4

Unchanged O

O

i B

½75


Cl

120
C, 3hr B

O

½76


C3F7 172
C,12hr

O 30%

n-C3F7H

i, n-C3F7Li, −50
C, Et2O

n-C3F7Li

(Me2N)2BX

10.27A

25%

½76


(Me2N)2BC3F7 10.27B

Figure 10.27

i

Me2Sn(CF=CF2)2

CF2=CFBCl2 + Me2SnCl2

½77


93% i, BCl3, rt SbF3 CF2=CFBF2 i

Me3SnC6F5

Me3SnBF2

+

59%

C6F5BF2

½78


i, BF3 CCl4 Me3SnC6F5

BCl3

C6F5BCl2

C6F5BF2

½78


Figure 10.28

C6F5BF2

+

KF

H2O

K(C6F5BF3) 10.29A

Figure 10.29

300
C

KBF4

+

-(C6F4)-n 10.29B

½79


Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 379

Organometallic Compounds 194
C

C6F5BF2

BF3

+

379

½78


(C6F5)2BF

18hr H2O

(C6F5)2BOH

F

71%

Figure 10.30

The increased susceptibility to hydrolysis of the fluorocarbon derivatives over their hydrocarbon analogues is illustrated by pentafluorophenylboronic acid which is stable in acid solution, whilst pentafluorophenyl is rapidly lost in neutral or basic solution [78] (Figure 10.31). i

C6F5BCl2

C6F5B(OH)2

H2O

C6F5B(OH)2.OH2

½78


89%

i, H2O, Acetone, −78
C

Base

H2O

C6F5H + H3BO3

C6F5B(OH)3

Figure 10.31

Tris(pentafluorophenyl)boron forms etherates but it can also be obtained uncoordinated in a hydrocarbon solvent (Figure 10.32). i

(C6F5)3B

3 C6F5Li + BCl3

½46


50%

i, Pentane/Hexane, −78
C to rt 3 C6F5MgBr + BF3.OEt2

i

(C6F5)3B

80%

½81


i, Toluene, Reflux

i (C6F5)3B

(C6F5)4BLi

½46


ii

i, C6F5Li, Et2O, Hexane, −78
C ii, Pyridine

(C6F5)3B.NC5H5

Figure 10.32

The contrast in thermal stability between ðC6 F5 Þ3 B and CF3 BF2 is significant; for example, the pentafluorophenyl compound was recovered largely unchanged after heating at 2708 C for 168 h [82]. Tris(pentafluorophenyl)boron is, in effect, a novel Lewis acid and it is a curious fact that this compound, which was first made over 40 years ago, has

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 380

380

Chapter 10

only in the last few years become important as a co-catalyst for polymerisation [18]. Similarly, pentafluorophenylaluminium compounds have been developed for the same purpose (see below), a salutary lesson to those who feel confident in predicting which basic research areas will yield great practical returns on the sums invested.

B Aluminium Factors analogous to those which limit the stability of perfluoroalkylboron compounds are even more dominant in the case of aluminium. Indeed, no perfluoroalkyl derivatives of tri-covalent aluminium have been obtained, although salts of the type Li½ðn-C3 F7 Þ2 AlI2
are produced [83] in reactions of perfluoroalkyl iodides with LiAlH4 . Tris(trifluorovinyl)aluminium may be obtained as the trimethylamine complex, as indicated in Figure 10.33. Et2O

3(CF2=CF)2Hg + 2Me3N.AlH3

½84


(CF2=CF)3Al.NMe3

+

3H2 + 3Hg

Figure 10.33

Tris(pentafluorophenyl)aluminium is obtained as the etherate from either the Grignard reagent in ether or the lithium derivative in ether/hexane [81, 85], whereas only complex materials are obtained from pentafluorophenyl-lithium in hexane (Figure 10.34). Attempts to remove the ether from the etherate, 10.34A, inevitably led to explosions. 3C6F5MgBr + AlBr3

Et2O −20 to 0
C

(C6F5)3Al.OEt2

½81, 85


10.34A

Figure 10.34

However, two pentafluorophenylaluminium derivatives, 10.35A and 10.35B, have been isolated [85] by cleavage of the mercurial (Figure 10.35). Both 10.35A and 10.35B eventually explode violently on heating and this occurs with 10.35A at about 1958 C. Nevertheless, the relative stability of these uncomplexed fluorocarbon derivatives may be attributed to bromine bridging, which saturates the covalency of aluminium and inhibits migration of fluorine from carbon to aluminium. Evidence from NMR spectra indicates either structure shown in Figure 10.36 for compound 10.35A. C6F5HgMe + AlBr3

i

i, Petroleum, 70
C, 5days

C6F5AlBr2 + MeHgBr 10.35A C6F5HgMe (C6F5)2AlBr + MeHgBr 10.35B

Figure 10.35

½85


Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 381

Organometallic Compounds C6F5 Al Br

Br Br Al Br C6F5

C6F5 Al C6F5

381

Br Br Al Br Br

Figure 10.36

Pentafluorophenylaluminium dibromide reacts with acid halides to form ketones [85], but more significant are its reactions with propene; an insertion reaction occurs, giving a polymer containing fluorine, after hydrolysis. Additionally, there is evidence to suggest the intermediacy of a p-bonded species 10.37A, since addition of toluene displaces some propene [86] (Figure 10.37). C6F5AlBr2 + MeCH=CH2

C6F5Al(C3H6)Br2 +

CHMe

½86


Al CH2 10.37A

Hydrolysis

Toluene C6F5(C3H6)nH + C3H6 + C6F5H

MeCH=CH2

Figure 10.37

Tris(pentafluorophenyl)aluminium has been prepared by metathesis, [87] (Figure 10.38), and the toluene complex is used as a co-catalyst for alkene polymerisation. Me3Al + B(C6F5)3

Me3B + (C6F5)3Al

½87


Figure 10.38

V

SILICON AND TIN

A

Silicon

The Grignard or lithium route is of limited value for the preparation of perfluoroalkyl derivatives. Much of the early work was concerned with the addition of silanes to fluorinated alkenes [88, 89], leading to the preparation of important fluorinated polysiloxanes, manufactured by Dow Corning Co. (Figure 10.39). The siloxane 10.39A chars at 150–2008 C and 10.39B decomposes above 2008 C to give vinyl fluoride, while 10.39C only decomposes at temperatures in excess of 4008 C. Trapping experiments (see Chapter 6, Section IIIA) have shown that a-elimination occurs to give carbenes, and therefore both of the elimination processes shown in Figure 10.40 must be factors which limit the thermal stability of siloxanes 10.39A and 10.39B. Trimethyltrifluoromethylsilane, which is now generally referred to as ‘Ruppert’s reagent’ [92], has been widely investigated [93–96] as an intermediate for transferring the trifluoromethyl group as a nucleophile, thus compensating for the deficiencies of polyfluoroalkyl Grignard or lithium derivatives. This approach also complements other methods for transfer of trifluoromethide ion. A variety of procedures have now been developed for the synthesis of this compound but the electrochemical procedure [93]

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 382

382

Chapter 10

(Figure 10.41), or simply heating bromotrifluoromethane with ðCH3 Þ3 SiCl and aluminium powder, is particularly effective [97] (Figure 10.42). Et2SiCl2 + n-C3F7Li

hν

MeSiHCl2 MeCl2Si

~ −50
C

Et2Si(n-C3F7)2

10%

+ Et2Si(n-C3F7)Cl

17%

+

MeCl2Si

+ CF2=CF2

½34


H

½90


MeCl2SiCF2CF2 MeSiHCl2 H2O

[MeSi(CF2CF2H)O]n hν

SiHCl3 + CF2=CF2

MeCl2SiCF2CF2H + MeCl2Si H2O

HCF2CF2SiCl3

etc

[HCF2CF2SiO1.5]n

½91


10.39A hν

SiHCl3 + CF2=CH2

H2O

HCF2CH2SiCl3

[HCF2CH2SiO1.5]n

½91


10.39B hν

SiHCl3 + CF3CH=CH2

H2O

CF3CH2CH2SiCl3

[CF3CH2CH2SiO1.5]n

½91


10.39C

Figure 10.39

Si

∆

C

Si

F +

C

F

C

∆

C

Si

Si

F +

F

Figure 10.40 i

CF3Br

Me3SiCF3

½93


i, Me3SiCl, anisole - HMPA (5 : 1) Sacrificial Al anode, Bu4NPF6 ( electrolyte) CF3Br + 2e −

CF3

+

+

−

Br

−

Me3SiCF3 + Cl

Me3SiCl

Anode: 2/3 Al0

Figure 10.41

−

CF3

2e

2/3 Al3+

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 383

Organometallic Compounds CF3Br

+

i

Me3SiCl i,

62%

Me3SiCF3

383

½97


Al powder, NMP, Heat

Figure 10.42

Displacement of perfluoroalkyl from silicon occurs, initiated by catalytic amounts of added fluoride ion, and reaction is especially effective with carbonyl sites as electrophiles. The process that has been established is outlined in Figure 10.43 [94]. O C R1

+

½94


CF3SiMe3

2

R

−

F3C

NBu4 F

R1

FSiMe3

OH R2

H+

CF3SiMe3

F3C

O

R1

R2

NBu4 F3C

TMS

R1

R2 O

F3C Me

Si

F3C

O

R1

R2

C R1

Me

R2

Me NBu4

Figure 10.43

Examples of the application of Ruppert’s reagent are shown in Figure 10.44, including the especially interesting diastereoselective procedures. The process and mechanism for nucleophilic transfer from Me3 SiCF3 to electrophilic sites are analogous to the clever use of DMF as a reservoir for trifluoromethide (10.45A), formed by reaction of fluoroform with a base [96], in a process outlined in Figure 10.45; they are also analogous to the use of iodoperfluoroalkanes with tetrakis(dimethylamino)ethene [99] (Figure 10.46). Not surprisingly, trifluorovinyl groups are cleaved by aqueous potassium hydroxide from, for example, ðCF2 5CFÞ4 Si, Et2 SiðCF5CF2 Þ2 and Et3 SiCF5CF2 , which may be obtained by the Grignard or lithium routes [100–104] (Figure 10.47). However, with other nucleophiles attack also occurs at carbon in 10.48A, leading to displacement of fluorine [102] (Figure 10.48).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 384

384

Chapter 10 i, ii

RCOOCH3

½94


RCOCF3

i, Me3SiCF3, THF, TBAF, −78
C

R = Ph = C6H11

ii, H+ R1

Ph

R1

Ph

i 2

R

78% 72%

R2

F3C

½94


41 − 86%

N

N

SiMe3 i, Me3SiCF3, THF, TBAF O

O

H i

R1

S N

t-Bu

CF3

t-Bu

½94, 98
R1

S N H

i, Me3SiCF3, THF, TBAF, −55
C

Yield

R1 = p-ClC6H4

(RS1S)/(RS1R)

95%

>99

= Ph

80%

97 : 3

= t-Bu

75%

99 : 1

Figure 10.44 i

Ph2CO + CF3H

Ph2C(OH)CF3 i, (Me3Si)3N / Me4NF,

72%

DMF

N(SiMe3)3 O

Me2N

Me3SiF

H

R1 R

F3C

N(SiMe3)2 CF3H

N(SiMe3)3 N

O F3C

O

NMe2 H 10.45A

M

O

CF3 R

O

F3C R1

R1 R + Me2N

O R

Figure 10.45

½96


OSiMe3

F

R1

O H

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 385

Organometallic Compounds

385

RFSiMe3

½99


+1e i RFI

+

TDAE

ii

[RFI]

RF

Transfer

55−81%

i, (Me2N)2C=C(NMe2)2 ii, Me3SiCl RF = C2F5, n-C3F7, n-C4F9

Figure 10.46

CF2=CFMgI

SiCl4

15%KOH

(CF2=CF)4Si

−15
C

−110
C

CF2=CFH

½100


Figure 10.47

Et2O

Et3SiCF=CF2 + RLi

Et3SiCF=CFR + LiF

10.48A

R = Ph

½102


76%

= C4H9

79%

Figure 10.48

B

Tin [15]

Some syntheses of perfluoroalkyl and polyfluoroalkyl derivatives are shown in Figure 10.49. hν Me3SnSnMe3

+ RFI

Me3SnRF

or ∆

½25, 105


+ Me3SnI

RF = CF3, C2F5, etc 90
C

n-Bu2SnH2 + 2CF2=CF2

Me3SnSnMe3

4hr

+ CF2=CF2

Me2SnCl2 + Mg

i

hν

n-Bu2Sn(CF2CF2H)2

Me3SnCF2CF2SnMe3 Me2Sn(C2F5)2

34%

28%

½106


½107
½108


i, C2F5I, THF, rt

Figure 10.49

A few general trends can be traced from reactions of these compounds. Hydrolytic cleavage occurs readily and this may well involve a two-step process, that is, via a fiveco-ordinate species, such as 10.50A, rather than an SN 2-type process (Figure 10.50). Nucleophilic displacement of trifluoromethyl also occurs with iodide ion and this is a useful method for generating difluorocarbene [109] (Figure 10.51) (see Chapter 6, Section

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 386

386

Chapter 10 HO

+

Me3SnCF3

[(Me3Sn(OH)CF3] 10.50A CF3H

+

Me3SnOH

+ OH

Figure 10.50

i I

Me3SnI +

+ Me3SnCF3

½109


CF3

i, NaI, DME, 80
C −F F

F ii

CF2

Me

Me Me Me

ii, Me2C=CMe2

Figure 10.51

IIIA), although other perfluoroalkyltin compounds are not sources of the corresponding carbenes [110]. Thermal decomposition, again, occurs readily and, in the case of ðCH3 Þ3 SnCF3 , difluorocarbene is probably formed (Figure 10.52); see Chapter 6, Section IIIA, Subsection 3. CF2=CF2 Me3SnCF3

150
C

Me3SnF +

CF2 F

Figure 10.52

Trifluorovinyl and pentafluorophenyl derivatives of tin [11, 15] can be obtained readily via magnesium or lithium derivatives. It is interesting that the stability of ðCH3 Þ3 SnC6 F5 to hydrolysis is very dependent on purity; in the presence of fluoride ion, rapid hydrolysis occurs and a process involving initial co-ordination of fluoride ion, and other halide ions, to tin has been suggested [111] (Figure 10.53). −

[Me3(C6F5)SnX]

−

Me3SnOH + C6F5H + X

Figure 10.53

½111


−

Me3SnC6F5 + X

−

[Me3(C6F5)SnX (H2O)]

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 387

Organometallic Compounds

387

Perfluorovinyl [112] and perfluoromethyl derivatives apparently undergo similar cleavage with aqueous alcoholic potassium fluoride. Fluorocarbon tin compounds may be used effectively in Stille coupling processes [15] (Figure 10.54). CF=CF2

I

½15


i

Bu3SnCF=CF2 +

Y

Y

15−87%

i = Pd catalyst

Figure 10.54

Electrophilic cleavage of perfluorovinyl [42] and perfluorophenyl [111] from mixed compounds occurs quite readily, although electrophilic attack is much more difficult in the tetrakis derivatives such as tetrakis(pentafluorophenyl)tin. The order of ease of electrophilic cleavage from tin has been established as CF2 5CF  C6 H5 > CH2 5CH > alkyl > perfluoroalkyl [42], and p-MeC6 H4 > C6 H5 > C6 F5 > Me [111], illustrating the effect of electron withdrawal by fluorine; nevertheless, quantitative work on the acid cleavage of Me3 SnC6 F5 indicates a rate greater than might be expected from the combined effects of the atoms on an additive basis [113]. The well-known exchange reaction between tetra-alkyl- or tetra-aryl-tin compounds and tin(IV) is much more difficult with tetrakis(pentafluorophenyl)tin [114] (Figure 10.55). 160
C

3(C6F5)4Sn + SnCl4

3(C6F5)3SnCl

7days

(C6F5)4Sn + 3 SnCl4

140
C 11 weeks

4 C6F5SnCl3

½114


½114


Figure 10.55

The trichloride is more effectively made by cleavage of methylpentafluorophenylmercury [111] (Figure 10.56). C6F5HgMe + 3 SnCl4

20
C 20 hours

C6F5SnCl3 + MeHgCl

½111


Figure 10.56

Cleavage of tetrakis(pentafluorophenyl)tin does not occur with boron halides, but pentafluorophenylboron halides can be obtained from ðCH3 Þ3 SnC6 F5 [79].

VI

TRANSITION METALS

Factors affecting the stability of transition-metal bonds to carbon are of continued interest and fluorocarbon transition-metal derivatives are especially interesting [115–117] because of their generally enhanced stability, relative to hydrocarbon analogues. Factors

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388

Chapter 10

that could enhance stability include the electronegativity of fluorocarbon groups, which will tend to increase the energy gap between s and s orbitals in the bonds to transition metals. Also, a factor which may limit stability in some hydrocarbon systems is the ease of migration of hydrogen to the metal, e.g. in platinum or palladium derivatives, whereas migration of fluorine may be more difficult if the strength of the carbon–fluorine bond is the rate-limiting step. Alkenyl and aryl derivatives of transition metals are generally more stable than the corresponding alkyl derivatives. This has been attributed to the unsaturated groups being able to accept charge from the metal via p orbitals. This process should be enhanced by the introduction of fluorine or fluorocarbon groups into the alkene or aromatic compound. For a wider discussion of fluorocarbon–transition-metal derivatives, and aspects such as their bonding, the reader is referred to other sources [115–117].

A Copper [14, 15] Fluorocarbon derivatives of copper have been studied quite widely, probably because there is little evidence for the elimination of metal fluoride being a limitation in these systems. Early work [118] showed that when perfluoroiodoalkanes are heated with copper in DMSO or DMF, then the copper compounds are formed in solution and these have been successfully applied in a variety of coupling reactions. High-dielectric media are essential to the success of these processes (Figure 10.57). Alternative procedures involve intermediate formation of copper derivatives via decarboxylation of salts of carboxylic acids [123–125] (Figure 10.58). It was concluded, from the establishment of a crude r-value of þ0.46 for the reaction, that the process may involve ½CF3 CuI
 as an intermediate. A similar process may be involved in the reaction of trifluoromethanesulphonyl chloride with copper (Figure 10.59). Burton and co-workers, as part of a series of ground-breaking studies on fluorinated organometallic systems [14], have established that trifluoromethyl derivatives may be obtained by reaction of halofluoromethanes with copper and other metals. The process involves electron transfer from the metal, with subsequent loss of halogen to form difluorocarbene which, in turn, generates very active fluoride ion by reaction with the solvent. The full process is indicated in Figure 10.60. In an analogous manner trifluoromethylcopper has been generated from sulphonyl fluorides (Figure 10.61). Trifluorovinylcopper reagents are also stable and have been used in various useful coupling reactions [15], especially in the synthesis of polyenes, where stereospecific systems may be obtained (Figure 10.62). Several procedures have been used to obtain pentafluorophenylcopper and this reagent (again, much more stable than phenylcopper) may be used in coupling procedures (Figure 10.63).

B Other metals Various approaches to other transition-metal derivatives have been applied which are not covered here, but some involve reactions that exploit the properties of the fluorocarbon

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 389

Organometallic Compounds

i

CF3I + Cu

PhI

[CF3Cu]

389

½118


PhCF3

i = DMF, ~135
C i

½119


n-C6F13I N

Br

Br

N

n-C6F13

n-C6F13

i = Cu, DMSO, 125−130
C i

I(CF2)3I + 2 ICHCHCl

ClHCCH(CF2)3CHCHCl

½120


i = Cu, Pyridine, 100
C CHF2Cu + CH

i

CCMe2Cl

HCF2CHCCMe2

½121


78%

i = DMF, −55
C i CF3Cu

+

I

½14


S

S

CF3

i = DMF, HMPA, 70
C NH2

NH2 N CF3Cu

+

N

N

i

I

½122


N

F3C N

N

N

AcO

N

AcO O

OAc

O

OAc

OAc

OAc

i = HMPA

Figure 10.57 i CF3CF2CO2Na + p-ClC6H4I

p-ClC6H4CF2CF3

i = DMF, HMPA, 170
C, Cu2I2

½125


54%

Figure 10.58

systems, particularly the propensity of unsaturated fluorocarbons to undergo nucleophilic attack as illustrated in Figure 10.64. Oxidative additions to iodoperfluoroalkanes proceed readily, whilst the additions to fluorinated alkenes shown in Figure 10.65 may well be radical processes. The important range of palladium-induced coupling processes [137] is not lost to fluorine chemistry: some illustrations are given in Figure 10.66.

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 390

390

Chapter 10 CF3

Cl

NO2

NO2

½126


i

CF3SO2Cl + Cu +

NO2

NO2 i = DMAC, Heat

Figure 10.59 CF2XY + M (Zn, Cd, Cu) [ CF2]

CF3

½14


Me2NCHF F

+ [ CF2] +

[ CF2]

Me2NCHF2 + CO

Me2NCHO

Me2NCHF2 F

MXY +

CF3

MXY

CF3MX + (CF3)2M

Figure 10.60 i

FSO2CF2I + PhI

½127


PhCCF3 80%

i = Cu, DMF, 60−80
C. ~6Hr. i FSO2CF2COOMe

ii [CuCF3]

i, CuI, DMF/HMPA, Pd(PPh3)4 ii, PhCHCBr2

PhCHC(CF3)2

½128


55 %

Figure 10.61

The effect of fluorinated systems on the reaction process shown in Figure 10.67 is of interest [139]; it is to be noted that insertion of the palladium catalyst into the carbon– halogen bond may be considered as a nucleophilic attack by the palladium centre, albeit a soft nucleophile, which prefers to attack C2Br over C2F [138]. This process is, of course, aided by the presence of electron-withdrawing groups (EWG) in the organic system. It is likely, however, that co-ordination of the other reactant, e.g. alkyne, to the palladium is the rate-determining step [137], but this will be aided by EWGs attached to the metal. It also appears that the metal can act as a nucleophile in reactions of certain nickel complexes with polyfluoro-aromatic compounds [145–147]. Surprisingly, with pentafluoropyridine, insertion occurs at the 2-position [145], which is in direct contrast with reactions of most other nucleophiles with this system (see Chapter 9), where

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 391

Organometallic Compounds F3C

F

F3C

F

F3C

Cu

Ph

I

F

F Ph

F

391

F

½15


CF3 54%

F

½15


F Cu

CF2=CFCu

CF3C

CCF3

F CF3

F3C I2 F

F I

F CF3

F3C 63%

½129


(CF2)n (CF2)n (CF2)n I

Cu

(CF2)n

(CF2)n

I (CF2)n n = 2, 3

Figure 10.62 C6F5I

½15


Activated Cu C6F5M + CuX M = Li, MgBr, CdX X = Cl, Br, I

C6F5Cu

C6F5H + LiCuMe2

60
C C6F5COOCu

C6F5Cu + CF2CFI

C6F5Cu + CH2I2

Figure 10.63

C6F5CFCF2

(C6F5)2CH2

88%

½15


70%

½15


Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 392

392

Chapter 10

CF3CF=CF2

THF

π-C5H5Fe(CO)2Na

½130


CF3CF=CFFe(CO)2πC5H5 + NaF (CO)5MnCF2CF=CF2

CF2=CFCF2Cl

(CO)5Mn M

½131; 132


M = Li, Na (CO)5MnCF=CFCF3 C6F6 +

C6F5Ru(CO)2π-C5H5

[π-C5H5Ru(CO)2]

½133


Figure 10.64

π-C5H5Co(CO)2 + CF3I

Benzene

π-C5H5Co(CO)(CF3)I + CO

½134


MeCF2CF2Re(CO)5

½135


(Ph3P)2Pt(CF=CFCl)2

½136


hν

MeRe(CO)5 + CF2=CF2

Benzene

(Ph3P)4Pt + CF2=CFCl

Figure 10.65

X F

X F

F

½138, 139


F

i N

Br

Br

RC

C

N

C

CR

R = Ph, C3H7

X = Br, CF(CF3)2 i = RC

CH, CuI, (Ph3P)3PdCl2 , Et3N CF=CF2 i

CF3CFH2 + ZnCl2 i = LDA, THF, 15−20
C ii = RC6H4I, Pd(PPh3)4, Heat

[CF2=CFZnCl]

½140


ii

R 61−86%

Figure 10.66 Contd

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 393

Organometallic Compounds Ar

F

H

Br

i

Ar

F

H

Br

Ar

ii

½141


Ph

H

100% Z isolated, 73%

High E/Z ratio

E/Z ~1:1

F

393

Ar = p-FC6H4i, −20
C, 7 days ii, PhSnBr3, Pd[(PPh3)]4, CuI, DMF, rt

F

F Bu3Sn

CF2CF

SiMe3 i,

½142


F

F

i

+ CF2=CFI

SiMe3

Pd[(PPh)3]4, CuI, DMF, rt

Ph

F

H

Br

Ph

i, ii

Br

Ph

F

H

H

½143


+ H

E/Z 1:1

F 100% Z

i, iii

i, Cl2Pd(PPh3)2 ii, HCOOH, n-Bu3N, DMF, 35
C iii, CO, 160psi, n-BuOH, n-Bu3N, 70
C

Ph

COO n-Bu

H

F

I

4

½144


i R

4

RF

R i, PdCl2[PPh3]2 , Et3N, CuI

RF

Figure 10.66 Contd

selective 4-attack occurs. It is tempting to invoke interaction with the ring nitrogen as a directing influence in these processes, even though the nitrogen is essentially non-basic in the ground state, although this will change as the reaction proceeds and charge develops on the nitrogen atom. Consequently, these processes may be used to approach aromatic substitution patterns that would be difficult to obtain with other systems, and the potential would be considerable if these processes could be achieved in a catalytic way (Figure 10.68).

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 394

394

Chapter 10 X

X F

F

F

F

½139


L2Pd(0) N

N

Br

Br

Br

R

X

X

F

L2Pd(II) N

F

F

Br

L2Pd(II)

F

N

Br

Br R X

Et3NHBr

R

H

F

F

Et3N L2Pd(II) N

H

X = Br, CF(CF3)2

R

Br

Br

L = Ph3P

Figure 10.67

i

F N

½145


HCl

F

F

PEt3

N

N

Ni

Et3P

H

F

i, Ni(COD)(PEt3)2 F

Et3P Ni i F

F

i, Ni(COD)(PEt3)2

Figure 10.68

Heat [Complex]

F

F

PEt3

½146


Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 395

Organometallic Compounds

395

Selective insertion into C2Cl occurs in competition with C2F, leading to further useful processes (Figure 10.69).

[Ni(COD)2]

F

PEt3

F

½147


N

Cl

N

Et3P

Ni

PEt3

Cl I2 I

MeLi −[Ni] N F

F N Et3P

Ni

PEt3

Me O

CO −[Ni] Me

F N

PEt3

H

O Me

F N

Figure 10.69

REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

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398

107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147

Chapter 10

M.A.A. Beg and H.C. Clark, Chem. Ind., 1962, 140. F.G.A. Stone and P.M. Triechel, Chem. Ind., 1960, 837. D. Seyferth, H. Dertouzos, R. Suzuki and J. Y.-P. Mui, J. Org. Chem., 1967, 32, 2980. W.R. Cullen, J.R. Sams and M.C. Waldman, Inorg. Chem, 1970, 9, 1682. R.D. Chambers and T. Chivers, J. Chem. Soc., 1964, 4782. D. Seyferth, G. Raab and K.A. Bra¨ndle, J. Org. Chem., 1961, 26, 2934. C. Eaborn, J.A. Treverton and D.R.M. Walton, J. Organometal. Chem., 1967, 9, 259. J.M. Holmes, R.D. Peacock and J.C. Tatlow, J. Chem. Soc. (A), 1966, 150. F.G.A. Stone in Fluorine Chemistry at the Millenium, ed. R.E. Banks, Elsevier, Amsterdam, 2000, p. 449. J.A. Morrison, Adv. Inorg. Radiochem., 1983, 27, 293. R.P. Hughes, Adv. Organometallic Chem., 1990, 31, 183. Y. Kobayashi, I. Kumadaki, S. Sato, N. Hara and E. Chikami, Chem. Pharm. Bull. (Tokyo), 1970, 18, 2334. G.J. Chen and C. Tamborski, J. Fluorine Chem., 1990, 46, 137. P.L. Coe, N.E. Milner and J.A. Smith, J. Chem. Soc., Perkin Trans. 1, 1975, 654. D.J. Burton, G.A. Hargraves and J. Hsu, Tetrahedron Lett., 1990, 31, 3699. Y. Kobayashi, K. Yamamoto, T. Asai, M. Nakano and I. Kumadaki, J. Chem. Soc., Perkin Trans. 1, 1980, 2755. K. Matsui, E. Tobita, M. Ando and K. Koudo, Chem. Lett., 1981, 1719. J.N. Freskos, Synth. Commun., 1988, 18, 965. G.E. Carr, R.D. Chambers and T.F. Holmes, J. Chem. Soc., Perkin Trans. 1, 1988, 921. C.A. Heaton and R.L. Powell, J. Fluorine Chem., 1989, 45, 86. Q.-Y. Chen and S.-W. Wu, J. Chem. Soc., Perkin Trans. 1, 1989, 2385. F.-L. Qing, X. Zhang and Y. Peng, J. Fluorine Chem., 2001, 111, 185. F.W.B. Einstein, A.C. Willis, W.R. Cullen and R.L. Soulen, J. Chem. Soc., Chem. Commun., 1981, 526. P.W. Jolly, M.I. Bruce and F.G.A. Stone, J. Chem. Soc., 1965, 5830. W.R. McClennen, J. Am. Chem. Soc., 1961, 83, 1598. H.D. Kaesz, R.B. King and F.G.A. Stone, Z. Naturforsch, 1960, 15b, 763. T. Blackmore, M.I. Bruce and F.G.A. Stone, J. Chem. Soc. (A), 1968, 2158. R.B. King, P.M. Treichel and F.G.A. Stone, J. Am. Chem. Soc., 1961, 83, 3593. J.B. Wilford, P.M. Treichel and F.G.A. Stone, Proc. Chem. Soc., 1963, 218. M. Green, R.B.L. Osborn, A.J. Rest and F.G.A. Stone, J. Chem. Soc. (A), 1968, 2525. J. Tsuji, Palladium Reagents and Catalysts. Innovations in Organic Synthesis, WileyInterscience, New York, 1995. R.D. Chambers, C.W. Hall, J. Hutchinson and R.W. Millar, J. Chem. Soc., Perkin Trans. 1, 1998, 1705. R.D. Chambers, P.R. Hoskins, G. Sandford, D.S. Yufit and J.A.K. Howard, J. Chem. Soc., Perkin Trans. 1, 2001, 2788. R. Anikumar and D.J. Burton, Tetrahedron Lett., 2002, 43, 2731. J. Xu and D.J. Burton, Tetrahedron Lett., 2002, 43, 2887. C. Lim, D.J. Burton and C.A. Wesolowski, J. Fluorine Chem., 2003, 119, 21. J. Xu and D.J. Burton, Org. Lett., 2002, 4, 831. M.P. Jennings, A.E. Cook and P.V. Ramachandran, J. Org. Chem., 2000, 65, 8763. S.J. Archibald, T. Braun, J.A. Gaunt, J.E. Hobson and R.N. Perutz, J. Chem. Soc., Dalton Trans., 2000, 2013. T. Braun, L. Cronin, C.L. Hoggitt, J.E. McGrady, R.N. Perutz and M. Reinhold, New J. Chem., 2001, 25, 19. M.I. Sladek, T. Braun, B. Newmann and H.-G. Stammler, New J. Chem., 2003, 27, 313.

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 399

Index

acid fluorides elimination of COF2 , 146 acid strengths, 93, 98 aerosol fluorination, 37 alcohols, 254–7 acidity, 93 diols, 255–6 aldehydes reactions, 243 synthesis, 243 alkali metal fluorides use in synthesis, 27–31, 47–9 alkenes acidities, 115 addition of 1,3-dipoles, 212–13 addition of fluorine, 77–9 addition of HF, 76–7 addition of radicals, 196 cycloadditions, 205 electrophilic addition, 101, 191–6 nucleophilic attack, 174 oxidation, 200–201 polymerisation, 203–5 rearrangement, 176 alkoxides, 251–4, 257–8, 269 alkynes synthesis, 218–22 allenes, 218 allylic cations, 102–3 aluminium, see organometallics amides, 241 amine hydrofluorides, 62 reactions with epoxides, 69 amino-acids diazotisation, 74 reaction with hexafluoroacetone, 248 amorphous polymers, 204–5 anaesthetics, 6 anhydrides, 241–2 aromatic compounds, 296 carbene additions, 338 free radical attack, 338

Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

introduction of fluorine, 297–300 nitrene additions, 338 arynes, 346–9 aza-alkenes, 278–84 azabenzenoid compounds, 304–6, 315–32 azo compounds, 284 photolysis, 284 Balz-Schiemann reaction, 73, 108, 300–301 base strengths, 94 biological applications, 5 biotransformations, 9 bis(perfluoroalkyl)alkynes, 218 bistrifluoromethyl nitroxide, 278 bistrifluoromethylcarbene reactions of, 155–6 structure, 158 bistrifluoromethylthioketene, 274 bond energies, 13 boron derivatives, see organometallics bromine trifluoride, 51 bromofluoroalkanes reaction with phosphines, 123 synthesis, 41 bromopentafluorobenzene, 339 Burton, 123 caesium fluoroxysulphate, 57, 79, 82 capto-dative substituents, 209 carbanions, 15, 96, 107–10 effects of F, 109 formation by addition of fluoride ion, 186, 241 H/D exchange, 107, 109, 111, 114 internal return, 108 pentakis(trifluoromethyl)cyclopentadienyl, 111, 114 perfluorocyclopentadienyl, 110, 114 pKa values for methane derivatives, 109 s-complexes, 112 stable salts, 112, 113, 173 stereochemistry, 110

399

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 400

400

Index

carbanions, (cont’d) synthesis of iodo derivatives, 241, 253 trapping of intermediates, 173, 186–7, 241 see polyfluoroalkylation carbenes fluorocarbenes, 147–59 from haloforms, 147 from halo-ketones and -acids, 149 from organometallic compounds, 149, 157, 386 from organophosphorus compounds, 151 (perfluoroalkyl)carbenes, 154–6, 158 push-pull stabilisation, 344 structure, 156 via pyrolysis and fragmentation reactions, 151 carbocations, 15, 99 long-lived, 102–5 polyconjugated systems, 105 polyfluorobenzenium, 104 trifluoromethyl, 104–5 carbonyl compounds reactions with SF4 and derivatives, 66 fluorination, 58–60, 66 carboxylic acids, 236 pKa values, 93, 98, 236 strengths, 92, 98, 236 synthesis, 237–40 CFCs, 4 Charlton n valves, 91–2 chlorine-fluorine exchange, 24–7 catalysts, 24, 25 chlorine monofluoride, 51 chlorofluorocarbons, 4 synthesis, 24–7 chlorotrifluoroethene polymer, 6 ciprofloxacin, 7 cobalt trifluoride, 32, 297–8, 301 copper compounds, 346 coupling reactions, 216, 389–91 organometallics, 387–91 cubane derivatives, 210 cuneane derivative, 209–10 cycloadditions, 205–12 cyclobutadiene intermediates, 210, 354 cyclo-octatetraene derivatives, 210, 216, 354, 391 cyclopolymerisation, 205 Cytopt, 6

DAST, 63–5, 70 decarboxylation, 145–6, 171 defluorination electrochemical, 297 of perfluoroalkanes and cycloalkenes, 164–5 of trifluoroethanol derivatives, 146 using phosphorus compounds, 250 using SnCl2 , 247 using tetrakis(dimethylamino)ethene, 215 Demnumt fluids, 5, 262 Desflurane, 6 DFI, 65, 67 diazirines, 147, 284, diazo compounds, 147, 284, diazonium salts, 73, 108, 301 dications, 104–5 Diels-Alder reactions, 209–12, 214, 218 dienes, 214–18, 391 charge transfer salts, 218 electrophilic attack, 339 epoxidation, 217 heterodienes, 247 nucleophilic attack, 176, 217 photolysis, 218 strain, 176 diethylaminosulphur trifluoride, see DAST difluorocarbene, 148–51, 156–8 2,2-difluoro-1,3-dimethylimidazoline, see DFI diols, 255–6 dioxirane formation, 249 1,3-dipoles, 213 displacement of fluorine from aromatic compounds, 307–36 from fluorinated alkenes, 132–3 dithionylium salts, 73, 300 DOPA, 9 dyes, 12 ECF, 33–5, 61, 171 electrochemical fluorination, 33–5, 61, 266 electronegativity, 13 electronic effects, 13, 16, 169 electron pair repulsion, 109, 110 electron transfer processes formation of cyclopentadienylides, 114 oxidative fluorination, 61 see also single electron transfer electrophilic aromatic substitution, 94, 99, 100, 299 in pentafluorobenzene, 339 electrophilic fluorinating agents

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 401

Index

containing N–F bonds, 58 containing O–F bonds, 56 FITS reagents, 126 fluorine, 52, 299 electrophilic perfluoroalkylation, 126–9 elimination reactions, 137 a-eliminations, 147 b-eliminations, 137–47 conformational effects, 140–41, 143 effect of leaving halogen, 137 ElcB processes elimination of hydrogen halide, 137 elimination of metal fluorides, 144 formation of alkenes, 169–71 formation of aromatics, 297–8 formation of carbenes, 147 formation of di-enes, 215–8 norbornyl systems, 145 polyfluorinated cyclic systems, 142 regiochemistry, 139 syn-/anti-elimination, 140 from trifluoroethanol, 146 enols, 251 epoxides, see oxiranes ethers iodoethers, 253 synthesis, 253 FAR reagents, see fluoroalkylamine reagents FEP, 6 FITS reagents, 126, 222 Flemiont, 5, 6 fluoride ion acid catalysis, 129–30 addition to alkenes, 77, 173 addition to alkynes, 77, 185 catalysts, 47–9 F/Cl rate constant ratios, 129 induced reactions, 185–91 as a leaving group, 128–31 oligomerisation of F-alkenes, 188–91 reactions with fluoroalkenes, 174, 253, 367 reactions with ketones, 251–4, 257–8 reactions with oxiranes, 257–8 rearrangements induced, 174, 187–8 solvents, 28, 48 source, 28, 49 synthesis of iodoperfluoroalkanes, 241 use in synthesis, 28–31, 47–50 see HALEX reactions see polyfluoroalkylation reactions with alkynes, 331–3

401

fluorinase, 10, 11 fluorinated alkenes LUMOs, 175 reactions with nucleophiles, 132, 171–85 reactions with transition metal anions, 368 reactivity order, with nucleophiles, 174 rearrangement by fluorine, 174 synthesis, 166 fluorinated alkynes stability, 169, 218 synthesis, 218–22 fluorinated allenes reactions, 219 synthesis, 218–19 fluorination alcohols, 62–6 alkenes, 56, 77–80 amino-acids, 54, 55 aromatic systems, 53, 57, 63 carbanions, 58 carbohydrates, 65 carbonyl compounds, 66–9 decalin, 53, 55 dicarbonyl comounds, 55, 57, 59, 62 esters, 58, 127 nitro compounds, 57 nitrogen-containing functional groups, 275 nucleosides, 59 oxidative, 61 phosphonates, 58 selective, 47 steroids, 53, 63, 66, 78, 79 thioethers, 72 fluorine aerosol fluorination, 37 bond energy, 35 control of reactivity, 36 as an electrophile, 52–4, 299 fluorine-18, 2 mechanism of fluorination, 35, 53–4 reaction with hydrazones, 75–6 replacement of hydrogen by fluorine, 51–5 selective fluorination, 51–5 stereochemistry of substitution, 53–5 use in synthesis of highly fluorinated compounds, 35–40 use of microreactors, 38 fluorine displacement addition-elimination mechanism, 131 F/Cl reactivity ratios at unsaturated sites, 131–2 influence of O and N substituents, 131

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 402

402

Index

fluorine displacement (cont’d) from unsaturated sites, 131–5 see nucleophilic aromatic substitution fluoroalkylamine reagents, 65–6 enantioselectivity, 65 mechanism, 66 use in supercritical CO2 , 65 fluoroalkynes, 218 fluoroaromatics aryne generation, 346–9 free radicals, 349–51 lithium derivatives, 345 synthesis, 296 valence isomers, 351–7 see nucleophilic aromatic substitution fluorodediazotisation, see Balz-Schiemann reaction 2-fluorodeoxyglucose, 7, 9 fluorodesulphurisation, 71–3 fluoroformates decarboxylation, 70, 71, 300, 302 fluoromethyl cations, 104 5-fluorouracil, 6, 7, 8 fluorous biphase techniques, 166 fluoroxy compounds, 258 synthesis, 259 fluorspar, 23, 24 Fluothanet (halothane), 6 Fomblint fluids, 5 frontier orbitals, 98 graphite fluoride, 39 HALEX process, 300, 303–6 halofluorination, 80–82 halogen exchange, 300, 303–6 halogen fluorides, 40, 80, 77, 72, 64, 62, 80–82 halonium ions, 105–7 halophilic processes, 123 halothane, 6 Hammett s values, 94–5, 100 heteroaromatic compounds boiling points, 306 polyfluoroalkylation, 327 synthesis, 298, 300–306 via cyclisation reactions, 332–5 heterodienes synthesis, 247, 355–7 hexachlorobenzene reaction with KF, 297 hexachlorobutadiene, 27 hexafluoro-2-butyne, 31, 220, 222

cycloadditions, 222, 224–6 formation of poly-enes, 331–3 free-radical additions, 226–7 polymerisation, 223–4 reaction with carbenes, 354 reactions with sulphur, 226 trimerisation, 296 hexafluoroacetone, 27–8, 243 cleavage, 248 formation of a dioxirane, 249 formation of heterodienes, 247 formation of peroxides, 248–9 reaction with water, 248 Wittig reaction, 250 hexafluorobenzene, 296–7 reaction with carbenes, 342–3 hexafluoropropene cycloadditions, 206, 211 formation of oligomers, 188 in polyfluoroalkylation, 327–8 radical additions, 197–204 reaction with SbF5 , 102 reaction with SO2 F2 , 272 reactions with electrophiles, 193–6 reactions with nucleophiles, 174, 177 sodium sulphite addition, 269 synthesis, 170–71 hexafluorothioacetone, 274 hexakis(trifluoromethyl)benzene, 296 HFCs, 4 high valency metal fluorides, 31 Hunsdiecker reaction, 240 hydrogen-deuterium exchange, 138–9 hydrogen fluoride, 23 additions to alkenes and alkynes 76–7, 193 amine hydrofluorides, 62, 68–70 cleavage of ethers and epoxides, 69, 71 diazonium salts, 73–4 electrochemical fluorination, 33–5 hazards, 23 reactions with azirenes and aziridines, 74–5 use in synthesis, 24 use with lead tetra-acetate, 61 hypofluorites, 56, 82 formation, 254 Ip effect, 98 imaging techniques, 7 imines, 275–6, 278–83 inductive effects, 94, 97, 169 industrial applications, 3 inert fluids, 4

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 403

Index

iodine pentafluoride, 271 fluorination of dicarbonyl compounds, 62 see iodoperfluoroalkanes iodoperfluoroalkanes formation of copper compounds, 389–91 formation of organometallics, 365–6, 368, 372–3 reactions with nucleophiles, 123–6, 194 synthesis, 41, 202–3, 241, 253 synthesis of alkynes, 221 2-iodoperfluorobutane, 125 2-iodoperfluoropropane, 241 Ishikawa reagent, 65, 66 Isofluranet, 6 ketones addition of fluoride ion, 251 enantioselective reduction, 10, 11 formation of heterodienes, 247 free-radical reactions, 250–51 protonation, 105 reactions, 243–54 synthesis, 243–5 kinetic acidities, 96, 111, 109, 113, 115 Krytoxt fluids, 5, 262 LaMar process, 36 lead tetra-acetate-hydrogen fluoride, 61 lithium derivatives, 345, 366–9 from alkenes, 369 from trifluoropropyne, 370 norbornyl derivatives, 145, 369 vinyl compounds, 370 lubricants, 5 Lumiflont, 5 macrocycles, 335 magnesium derivatives, 368 Meisenheimer s-complexes, 113 mercurials, 366, 373–6 generation of carbenes, 150 metal fluorides eliminations, 145 as fluorinating agents, 23–32, 47–9 microreactors, 38 Moissan, 2 monofluoroacetate, 9 Nafiont, 5, 6, 268 naturally occurring compounds containing C–F, 1 negative hyperconjugation, 16, 94–7

in perfluoroalkanes, 163 nickel insertion reactions, 394–5 nitrenes, 344 nitro groups displacement by fluoride ion, 75 nitrogen derivatives, 236, 275 nitrosoalkanes, 277 nitroxides, 278 nomenclature, 16–19 nonaflates, 265 norbornyl cation, 106 nucleophilic aromatic substitution from alkenes and cycloalkenes, 171–85 attack on nitrogen, 329 benzenoid compounds, 307–15 effect of acid, 324–5 effect of ring N, 315 fluoride-ion-induced reactions, 325–31 HOMO-LUMO interaction, 175 mechanism, 134, 307 orientation of substitution, 312–14, 319, 321–5 pyridine derivatives, 315–25 substituent effects of F, 312–14 nucleophilic displacement of halogen from fluorocarbon systems, 122 from alkanes, 132, 171–85 from arenes, 133, 307 from cycloalkenes, 171–85 effect of F substituents, 123 HOMO-LUMO interaction, 175 mechanisms, 123, 124 SN 1 SN 2 processes, 122 nucleosides fluorination, 59 Olah generation of stable carbocations, 102 Olah’s reagent, 62 oligomerisation of fluorinated alkenes, 188–91 organometallic compounds aluminium, 380–81 boron, 376–80 cleavage reactions, 366, 375–6, 380–81 copper, see copper from cyclo-alkanes, 369 mercury, 373–6 nickel insertion reactions, 394–5 norbornyl derivatives, 369 palladium coupling, 392–4 polyfluoroaryl, 367, 371

403

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 404

404

Index

organometallic compounds (cont’d) from polyfluoroiodoalkanes, 365–7, 368 tin, 366, 370, 375, 378, 385 transition metals, 387 via fluoride addition, 367 vinyl derivatives, 370 zinc, 371–3 oxetanes, 262 oxidation of F-alkenes, 260–61 using bis(trifluoromethyl)dioxirane, 249 using fluoroketones, 248–9 using peroxytrifluoroacetic acid, 242 oxiranes reactions with hydrogen fluoride, 69, 71, 180, 217, 254, 255 ring opening, 257, 263–4 synthesis, 259–61 oxygen derivatives, 236 ozone depletion, 4 palladium coupling, 392–4 PCTFE, 6 pentafluorophenyl compounds from hexafluorobenzene, 307 pentafluorophenyl group acidifying effect, 115 pentafluorophenyl lithium, 366 pentafluoropyridine carbene addition, 343 electrochemical reduction, 342 free radical attack, 340–41 polyfluoroalkylation, 327 synthesis, 297, 304 perchloryl fluoride, 60 perfluoro-2-butyne, 31 perfluoroacetic anhydride, 241 perfluoroacetone, see hexafluoroacetone perfluoroalcohols, 254–7 perfluoroalkanes, 162 by addition of fluorine to F-alkenes, 78 defluorination, 164–5 by direct fluorination, 35 fragmentation, 166 hydrolysis, 163 physical properties, 163 reaction with thiols, 127 structure and bonding, 162–3 using cobalt trifluoride, 32 perfluoroalkenes electrophilic attack, 191–6 epoxidation, 180

nucleophilic attack, 171–85 oligomerisation, 189 oxidation, 260 polymerisation, 203–5 radical addition, 196–205 structure and bonding, 167 synthesis, 164, 169–71 perfluoroalkyl effect, 97 perfluoroalkylation electrophilic, 126, 222 nucleophilic, 325 perfluoroallene, 219 Perfluorocycloalkenes cycloadditions, 210–14 formation of oligomers, 191 photochemistry, 189 radical additions, 200–201, 204 reactions with nucleophiles, 183–5 ring-opening, 168 perfluorocyclobutene, 168, 170, 201 perfluorocyclopentene, 31, 170, 200 perfluorodecalin defluorination, 165 reaction with thiols, 127, 165 perfluoroisobutene addition of diazamethane, 213 reactions with nucleophiles, 180 synthesis, 166, 170 perfluorooctyl bromide, 9 perfluorophenol, 98 perfluoropolyethers, 4, 5, 258, 269 perfluoroquinoline, see quinoline derivatives perfluoro-t-butanol, 71, 255 peroxides, 242, 264 peroxytrifluoroacetic acid, 242 PET scanning, 7, 9 PFA, 6 pharmaceuticals, 7 effects of F substitution, 7 phosphate mimics, 11 phosphonates, 11 phosphorus acids, 93 photochemistry formation of valence isomers, 351–7 photoelectron spectroscopy of fluorinated alkenes, 98 phthalocyanine complexes, 329 physical properties, 3 pi-inductive effect, 98 plant protecting agents, 9, 10 polyfluoroalkylation, 325 polyfluoroalkylcarbenes, 154–6

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 405

Index

polyfluorobenzenium cations, 104 polymers, 5, 203–5 polysulphides, 270 polytetrafluoroethene, 5, 6, 204, 260, 262 positron emission tomography, 7, 9 potassium fluoride, see HALEX process proton sponge, 49–50, 63 Prozact, 7, 8 PTFE defluorination, 164 see polytetrafluoroethene Pummerer-type processes, 51, 61 PVF, 6 pyridinium poly(hydrogen fluoride), 62, 68–9 pyrimidines, 13 pyrolysis of CHClF2 , 151 formation of carbenes, 151–4, 343 quinoline derivates perfluoroquinoline, 305–6 radical additions to fluorinated alkenes, 196–205 examples, 199 orientation, 197 rearrangement, 201 radical clock experiments, 54, 59–60 radicals addition to F-alkenes, 196–205 polarity effects, 117 relative stabilities, 116 Scherer radical, 117 stereochemistry, 116 substituents effects, 115–7 rearrangements Claisen, 256 of di-enes using SbF5 , 217 induced by fluoride, 185, 187–8 radicals, 201 see SN 20 processes thermal, 355 via valence isomers, 351–7 resonance effects, 94, 100 Ruppert’s reagent, 382–4 safety toxicity of fluorinated alkenes, 172 use of hydrogen fluoride, 23 use of perchloryl fluoride, 60 Scherer radical, 117 Scotchgardt, 12 Selectfluort, 58–60

Sevofluranet, 6 sigma, s, sþ values, 95, 100 silicon derivatives, 381–5 silver fluoride, 47 silver fluorine, 23 Simons, 2, 23 single electron transfer processes, 124, 125–6 SN 2 processes effect of substituents, 122 F/Cl rate constant ratios, 129 fluoride as a leaving group, 128 transition-states, 128 SN 20 processes, 176, 185 solvolysis reactions, 106 source of fluorine, 23 squaric acid, 130 stable radicals, 117 stereoselectivity addition of fluorine to alkenes, 56, 78–9 addition to enolates, 246 in direct fluorination, 53–4 in H/D exchange, 112 using DAST, 64–5 steric effects, 91, 246, 328, 371 in b-eliminations, 141 in SN 2 processes, 123 sulphides, 270–71 sulphonic acids, 265 by ECF, 266 polymerisable monomers, 260 sulphur derivatives, 265, 272 use in ethene recovery, 275 sulphur pentafluoride derivatives, 273 sulphur tetrafluoride, 63, 64, 66, 69–70 sulphur trioxide, cycloaddition, 214 surfactants, 12 Swarts, 2, 24 Taft Es values, 91–2 TAS-F, see tris(dimethylamino)sulphonium difluorotrimethylsiliconate tautomers, 251 Teflont, see PTFE Teflont AF, 6 telomerisation, 202–3 tetrabutylammonium fluoride, 49 tetrafluoroethene addition of electrophiles, 193–5 addition of sulphur trioxide, 268 cycloaddition, 205–12, 268, 277 formation of oligomers, 190

405

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406

Index

tetrafluoroethene (cont’d) in polyfluoroalkylation, 328 radical additions, 198, 202–4 reactions with nucleophiles, 173–4, 177 reaction with SO2 F2 , 272 reaction with sulphur, 270 sodium sulphite addition, 269 synthesis, 170 in triazine synthesis, 275 tetrakis(dimethylamino)ethene, 215 textile treatment, 12, 13 thiete formation, 226 thiocarbonyl compounds, 272 thiols fluorination, 272 tin, see organometallics toxicity, see safety transition metal derivatives, 368 triazines, 13, 275, 304, 329–30 1,2,3-triazines photolysis, 221 triflates, 265 triflic acid, 265–6 strength, 92 trifluoroacetic acid, 240 trifluoroethanol formation of CF2 derivatives, 146, 250 trifluoroiodomethane nucleophilic attack, 123 trifluoromethanesulphonic acid, see triflic acid trifluoromethanesulphonyl chloride, 267 trifluoromethanesulphonyl group, 267 trifluoromethoxide salts, 96

trifluoromethyl formation, 24 hydrolysis, 332 s values, 94–6 size, 92 transfer from CF3 H, 384 transfer from silicon, see Ruppert’s reagent trifluoromethylation transfer from CF3 H, 384 using Ruppert’s reagent, 382–4 trifluoromethylcarbene, 158 trifluoropropene electrophilic addition, 102 trifluoropropyne, 221 trioxide, 265 tris(dimethylamino)sulphonium difluorotrimethylsiliconate, 49–50 valence isomers, 222, 351–7 van der Waals radii, 91 volumes, 92 vinyl radicals, 117 vinyllithium derivatives, 366 Vitont, 6 wartime developments, 2 Wittig reaction, 250 xenon difluoride, 60, 80, 301 Yaravenko reagent, 65 ylides, 123